Imidazolothiazole compounds for the treatment of disease

ABSTRACT

Compounds, compositions and methods are provided for modulating the activity of receptor kinases and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by receptor kinases.

This application claims priority to U.S. provisional application Ser.No. 60/743,543, filed Mar. 17, 2006, entitled “ImidazolothiazoleDerivatives For The Treatment Of Disease”. The disclosure of the abovereferenced application is incorporated by reference herein in itsentirety.

FIELD

New small molecule compounds, compositions and methods for treatingdisease are provided. The compounds provided are modulators of activityof enzymes, such as kinases, and are useful in the treatment,prevention, or amelioration of a disease or disorder related to enzymeactivity or one or more symptoms thereof.

BACKGROUND

Protein kinases (PKs) are enzymes that catalyze the phosphorylation ofhydroxy groups on tyrosine, serine and threonine residues of proteins.Protein kinases, and in particular the receptor protein tyrosine kinase(RTK) family of protein kinases, act primarily as growth factorreceptors and play a central role in signal transduction pathwaysregulating a number of cellular functions, such as cell cycle, cellgrowth, cell differentiation and cell death. Aberrant or excessiveactivity or the disregulation of activity of receptor protein tyrosinekinase (RPTK) has been observed in many disease states including benignand malignant proliferative disorders as well as inflammatory disordersand immune system disorders that result from inappropriate activation ofthe immune system to cause, for example, autoimmune diseases.

Disregulated activity of the receptor tyrosine kinase of the plateletgrowth factor receptor (PDGFR) family, as one example, has beenimplicated in various proliferative disorders. Gene amplification orupregulation of PDGFR occurs in patients with gliomas or sarcomas(Kumabe et al., Oncogene, 7:627-633 (1992), Ostman and Heldin CancerRes. 80:1-38 (2001)). Constitutive activation of PDGFR-α has been foundin patients with chronic myelomonocytic leukemia (CMML) (Magnusson etal. Blood 100:1088-1091 (2002)). Gain of function mutations and smalldeletions in the PDGFR-α gene has also been found in patients withgastrointestinal tumors (GIST) (Heinrich et al. Science 299: 708-710(2003)) and in patients with idiopathic hypereosinophilic syndrome(Cools et al. N. Engl. J. Med. 348:1201-1214 (2003)). PDGFR-β has beenfound to be expressed in the tumor stroma in a majority of solid tumors,which makes this receptor a potential target for anti-tumor therapy(Pietras et al. Cancer Cell 3:439-443 (2003), Pietras et al. Cancer Res.62: 5476-5484 (2002)). PDGFR-β has also been found to be expressed intumor vasculature and studies have suggested PDGFR-β inhibition as onemechanism for anti-angiogenic therapy. (See, Bergers et al J. Clin.Invest. 111(9): 1287-1295 (2003), Saharinen et al. J. Clin. Invest.111:1277-1280 (2003)).

A second member of the PDGFR family, Flt3 (also called Flk2), plays animportant role in the proliferation and differentiation of hematopoieticstem cells and activating mutation or overexpression of this receptor isfound in AML (See, Heinrich Mini-Reviews in Medicinal Chemistry (2004)4(3):255-271, Kiyoi et al. Int J Hematol (2005) 82:85-92). More than adozen known Flt3 inhibitors are being developed and some have shownpromising clinical effects against AML (See Levis et al. Int J Hematol.(2005) 82:100-107). The Flt3 receptor is also expressed in a largeportion of dendritic cell progenitors and stimulation of the receptorcauses the proliferation and differentiation of these progenitors intodendritic cells (DC). Since dendritic cells are the main initiators ofthe T-cell mediated immune response, including the autoreactive immuneresponse, Flt3 inhibition is a mechanism for downregulating DC-mediatedinflammatory and autoimmune responses. One study shows the Flt3 inhibtorCEP-701 to be effective in reducing myelin loss in experimentalautoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis(See Whartenby et al. PNAS (2005) 102: 16741-16746). A high level of theFlt3 ligand is found in the serum of patients with Langerhans cellhistiocytosis and systemic lupus erythematosus, which further implicatesFlt3 signaling in the disregulation of dendritic cell progenitors inthose autoimmune diseases (See Rolland et al. J. Immunol. (2005)174:3067-3071).

A third member of the PDGFR family, colony-stimulating factor-1 receptor(CSF-1R) (also called macrophage colony stimulating factor receptor(M-CSFR) or fms) is expressed by many carcinomas of the breast and humanepithelial cancers, especially of the female reproductive tract(Kacinski (1997) Mol. Reprod. Dev. 46:71-74) and presents a potentialtarget for cancer therapies. High level of CSF-1 expression in solidtumors and leukemias, also suggests that CSF-1R might be a therapeutictarget for blood cancers and solid tumors (Haran-Ghera (1997) Blood89:2537-2545). A high level of CSF-1 expression is also found inLangerhans cell histiocytosis (Rolland et al. J Immunol. (2005)174:3067-3071).

Kit (or stem cell factor receptor, or SCFR) is another member of thePDGFR family, and the presence of kit mutations is a key diagnosticmarker for gastrointestinal stromal tumors (GIST) (Duensing et al.(2004) Cancer Investigation 22(1):106-116). Gleevec® (imatinib mesylateor STI571), the first FDA-approved RPTK inhibitor originally approvedfor c-Abl-mediated chronic myeloid leukemia, gained FDA-approval forKit-mediated GIST in 2002 and has validated the molecular-based approachof Kit inhibition for the treatment of GIST. (Giorgi and Verweij, MolCancer Ther 4(3):495-501 (2005)). Gain of function mutations of the Kitreceptor are also associated with mast cell/myeloid leukemia andseminomas/dysgerminomas (Blume-Jensen Nature 411(17): 355-365 (2001).Kit mutations have been also identified in certain melanomas andrecognized as a potential therapeutic target for melanoma (Curtain etal. J Clin. Oncol. 24(26):4340-4346 (2006)).

The vascular endothelial growth factor receptor (VEGFR) representsanother family of RTKs, one that is implicated in tumor angiogenesis.VEGF and its receptors VEGFR1 (also called Flt1) and VEGFR2 (also calledKDR) are overexpressed in the great majority of clinically importanthuman cancers including cancers of the gastrointestinal tract, pancreas,bladder, kidney, endometrium and in Kaposi's sarcoma. VEGFR2 is alsohighly expressed in certain intracranial tumors including glioblastomamultiforme and sporadic and von Hippel Landau (VHL) syndrome-associatedcapillary hemangioblastoma. There are currently more than a dozen VEGFR2inhibitors in clinical development for anti-angiogenic therapy (Paz andZhu, Frontiers in Bioscience 10:1415-1439 (2005)).

Another member of the VEGFR family, VEGFR3 (also called Flt 4) has beenidentified as a lymphangiogenic growth factor receptor which play a keyrole in the growth of new lymphatic vessels (lymphangiogenesis).Activation of the VEGFR3 signaling pathway has been shown to stimulatemetastatic spread of tumor cells (See Stacker et al. Nature Rev2:573-583 (2002)) and therefore its inhibition could be the basis fortreating conditions characterized by abnormal lymphatic vessel function(See Stacker et al. Current Pharmaceutical Design 10:65-74 (2004), Achenet al. British Journal of Cancer 94:1355-1360 (2006)).

Ret kinase is yet another RTK, one that is found expressed in medullarythyroid carcinoma, a condition that is part of the multiple endocrineneoplasia 2A and 2B (MENS 2A and 2B) syndromes. Ret is constitutivelyactive in medullary thyroid carcinoma (both familial and sporadic) andin papillary thyroid carcinoma. Some known RTK inhibitors havingRet-inhibitory activity have been shown to be effective in inhibitingtumor growth in nude mouse models (Stock et al., Cancer Res 63:5559-5563(2003)) and Carlomagno et al., Journal of the National Cancer Institute98(5):326-334 (2006)).

It is additionally possible that inhibitors of certain kinases may haveutility in the treatment of diseases when the kinase is notmisregulated, but is nonetheless essential for maintenance of thedisease state. In such cases, inhibition of the kinase activity wouldact either as a cure or palliative for these diseases. For example, manyviruses, such as human papilloma virus, disrupt the cell cycle and drivecells into the S-phase of the cell cycle (Vousden, FASEB Journal,7:8720879 (1993)). Preventing cells from entering DNA synthesis afterviral infection by inhibition of essential S-phase initiatingactivities, may disrupt the virus life cycle by preventing virusreplication. This same principle may be used to protect normal cells ofthe body from toxicity of cycle-specific chemotherapeutic agents (Stoneet al., Cancer Research, 56:3199-3202 (1996); Kohn et al., Journal ofCellular Biochemistry, 54:44-452 (1994)).

Finally, while overactivation of RTK signaling pathways is often theunderlying mechanism for cancer, impaired deactivation of RTKs such asthe impaired down-regulation of RTKs via ligand-induced endocytosis orimpaired negative feedback loops, may also be the cause of somemalignancies. Another strategy for use of the molecules discussed hereintherefore is to repair and promote any existing mechanism fordown-regulating RTKs.

In view of the large number of protein kinase inhibitors and themultitude of PK-mediated proliferative, inflammatory and immune functiondiseases, there is an ever-existing need to provide novel classes ofcompounds that are useful as PK inhibitors and thus in the treatment ofPK related diseases, as discussed herein.

SUMMARY

Compounds for use in medical treatment, pharmaceutical compositions andmethods for modulating the activity, binding or sub-cellulardistribution of kinases are provided. In one embodiment, the compoundsfor use in the compositions and methods provided herein have formula(I):

wherein

bond b is a single bond or double bond;

X is —S—, —N(R⁵)— or —O—;

Z¹ and Z³ are each independently —N(R⁵)—, —(CH₂)_(q), —O—, —S—, or adirect bond;

Z² is —C(O)— or —C(S)—;

m is an integer from 1 to 2;

n is an integer from 1 to 3;

each q is independently an integer from 1 to 4;

R⁰ is hydrogen, halo, hydroxy, optionally substituted alkyl, oroptionally substituted alkoxy;

each R¹ is independently selected from the group consisting of halo,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheteroaralkyl, optionally substituted heteroaralkenyl, —R⁶OR⁷, —R⁶SR⁷,—R⁶S(O)_(t)R⁸ (where t is 1 or 2), —R⁶N(R⁷)₂, —R⁶OR⁹OR⁷, —R⁶CN,—R⁶C(O)R⁷, —R⁶C(S)R⁷, —R⁶C(NR⁷)R⁷, —R⁶C(O)OR⁷, —R⁶C(S)OR⁷, —R⁶C(NR⁷)OR⁷,—R⁶C(O)N(R⁷)₂, —R⁶C(S)N(R⁷)₂, —R⁶C(NR⁷)N(R⁷)₂, —R⁶C(O)N(R⁷)R⁹N(R⁷)₂,—R⁶C(O)SR⁸, —R⁶C(S)SR⁸, —R⁶C(NR⁷)SR⁸, —R⁶S(O)_(t)OR⁷ (where t is 1 or2), —R⁶S(O)_(t)N(R⁷)₂ (where t is 1 or 2), —R⁶S(O)_(t)N(R⁷)N(R⁷)₂ (wheret is 1 or 2), —R⁶S(O)_(t)N(R⁷)N═C(R⁷)₂, —R⁶S(O)_(t)N(R⁷)C(O)R⁸ (where tis 1 or 2), —R⁶S(O)_(t)N(R⁷)C(O)N(R⁷)₂ (where t is 1 or 2),—R⁶S(O)_(t)N(R⁷)C(NR⁷)N(R⁷)₂ (where t is 1 or 2), —R⁶N(R⁷)C(O)R⁸,—R⁶N(R⁷)C(O)OR⁸, —R⁶N(R⁷)C(O)SR⁸, —R⁶N(R⁷)C(NR⁷)SR⁸, —R⁶N(R⁷)C(S)SR⁸,—R⁶N(R⁷)C(O)N(R⁷)₂, —R⁶N(R⁷)C(NR⁷)N(R⁷)₂, —R⁶N(R⁷)C(S)N(R⁷)₂,—R⁶N(R⁷)S(O)_(t)R⁸ (where t is 1 or 2), —R⁶OC(O)R⁸, —R⁶OC(NR⁷)R⁸,—R⁶OC(S)R⁸, —R⁶OC(O)OR⁸, —R⁶OC(NR⁷)OR⁸, —R⁶OC(S)OR⁸, —R⁶OC(O)SR⁸,—R⁶OC(O)N(R⁷)₂, —R⁶OC(NR⁷)N(R⁷)₂, —R⁶OC(S)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂,—R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)R⁹C(O)R⁷, —R⁶C(O)R⁹C(S)R⁷,—R⁶C(O)R⁹C(NR⁷)R⁷, —R⁶C(O)R⁹C(O)OR⁷, —R⁶C(O)R⁹C(S)OR⁷,—R⁶C(O)R⁹C(NR⁷)OR⁷, —R⁶C(O)R⁹C(O)N(R⁷)₂, —R⁶C(O)R⁹C(S)N(R⁷)₂,—R⁶C(O)R⁹C(NR⁷)N(R⁷)₂, —R⁶C(O)R⁹C(O)SR⁸, —R⁶C(O)R⁹C(S)SR⁸,—R⁶C(O)R⁹C(NR⁷)SR⁸, —R⁶C(O), —R⁶C(O)R⁹N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)R⁹N(R⁷)R⁹OR⁷and —R⁶C(O)N(R⁷)R⁹OR⁷;

each R² is independently selected from hydrogen, halo, nitro, cyano,optionally substituted alkyl, —OR¹², —SR², —N(R¹²)₂, —S(O)_(t)R¹³ (wheret is 1 or 2), —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², or—N(R¹²)S(O)_(t)R¹³ (where t is 1 or 2);

R³ is hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR¹²,—SR¹², —N(R¹²)₂, —S(O)_(t)R¹³ (where t is 1 or 2), —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —C(O)SR¹², or —N(R¹²)S(O)_(t)R¹³ (where t is 1 or 2);

R⁴ is selected from the group consisting of optionally substitutedalkyl, optionally substituted heterocyclyl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedcycloalkenyl and optionally substituted aryl;

each R⁵ is independently hydrogen, or optionally substituted alkyl;

each R⁶ is independently a direct bond, an optionally substitutedstraight or branched alkylene chain, or an optionally substitutedstraight or branched alkenylene chain;

each R⁷ is independently selected from (i) or (ii) below

(i) R⁷ is selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl, or

(ii) two (R⁷)s together with the atom to which they are attached form anoptionally substituted heterocyclyl or optionally substitutedheteroaryl;

R⁸ is independently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl;

each R⁹ is independently an optionally substituted straight or branchedalkylene chain or an optionally substituted straight or branchedalkenylene chain;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroaralkyl; and

R¹³ is independently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl.

In one embodiment, the compound is selected with the proviso that,

(i) if -Z¹Z²Z³R⁴ is —NHC(O)Bu then R¹ may not be ethoxy;

(ii) if -Z¹Z²Z³R⁴ is —C(O)OR_(p), where R_(p)=methyl, or ethyl, then R¹may not be hydroxyl, methoxy or methoxycarbonyl;

(iii) if -Z¹Z²Z³R⁴ is —NHC(O)C(O)OR_(p), where R_(p)=methyl, or ethyl,then R¹ may not be methoxy;

(iv) if -Z¹Z²Z³R⁴ is —CH₂C(O)OR_(p), where R_(p)=methyl, or ethyl, thenR¹ may not be methoxy or ethoxy;

(v) if -Z¹Z²Z³R⁴ is —OC(O)CH₃, then R¹ may not be methyl, methoxy orethoxy;

as a single isomer, a mixture of isomers, a racemic mixture of isomers,a solvate, a hydrate or a prodrug, or as a pharmaceutically acceptablesalt thereof.

In one embodiment, the compound provided herein is a pharmaceuticallyacceptable salt of the compound of formula (I). In one embodiment, thecompounds provided herein is a solvate of the compound of formula (I).In one embodiment, the compounds provided herein is a hydrate ofcompound of formula (I). In one embodiment, the compound provided hereinis a prodrug of the compound of formula (I).

Such compounds can bind to one or more kinases with high affinity andmodulate their activity. In certain embodiment, such compounds exhibitan EC₅₀, IC₅₀ or binding affinity of less than 1 μM, and in certainembodiments, less than about 0.5 μM, 250 nM, 100 nM or 50 nM. In oneaspect, the compounds provided herein are selective for a specifickinase, or specific subset of kinases, i.e. are at least 5, 10, or inanother aspect, at least 20, 50, 100 times more potent, as measured byany of the in vitro assays described herein, in binding to the desiredkinase(s) compared to a non preferred kinase or kinases. In one aspect,the compounds selectively inhibit the desired kinase(s) withoutsignificant effect on the non desired kinase(s).

Also provided are pharmaceutical compositions formulated foradministration by an appropriate route and means containing effectiveconcentrations of one or more of the compounds provided herein, orpharmaceutically acceptable salts, solvates, hydrates and prodrugsthereof, and optionally comprising at least one pharmaceutical carrier,excipient, vehicle, binder, diluent, disintegrating agent, lubricant,glidant, sweetening agent or flavoring agent.

Such pharmaceutical compositions deliver amounts effective for thetreatment, prevention, or amelioration of diseases or disorders that aremodulated or otherwise affected by protein kinases (PK related diseases)or one or more symptoms or causes thereof. Such diseases or disordersinclude without limitation:

A) Cancers, including, but not limited to head and neck cancer,(originating lip, oral cavity, oropharynx, hypopharynx, larynx,nasopharynx, nasal cavity and paranasal sinuses, salivary glands); lungcancer, including small cell lung cancer, non-small cell lung cancer;gastrointestinal tract cancers, including esophageal cancer, gastriccancer, colorectal cancer, anal cancer, pancreatic cancer, liver cancer,gallbladder cancer, extrahepatic bile duct cancer, cancer of the ampullaof vater; breast cancer; gynecologic cancers, including, cancer ofuterine cervix, cancer of the uterine body, vaginal cancer, vulvarcancer, ovarian cancer, gestational trophoblastic cancer neoplasia;testicular cancer; urinary tract cancers, including, renal cancer,urinary bladder cancer, prostate cancer, penile cancer, urethral cancer;neurologic tumors; endocrine neoplasms, including carcinoid and isletcell tumors, pheochromocytoma, adrenal cortical carcinoma, parathyroidcarcinoma and metastases to endocrine glands.

Further examples of cancers are basal cell carcinoma; squamous cellcarcinoma; chondrosarcoma (a cancer arising in cartilage cells);mesenchymal-chondrosarcoma; soft tissue sarcomas, including, malignanttumours that may arise in any of the mesodermal tissues (muscles,tendons, vessels that carry blood or lymph, joints and fat); soft tissuesarcomas include; alveolar soft-part sarcoma, angiosarcoma,fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibroushistiocytoma, hemangiopericytoma, mesenchymoma, schwannoma, peripheralneuroectodermal tumours, rhabdomyosarcoma, synovial sarcoma; gestationaltrophoblastic tumour (malignancy in which the tissues formed in theuterus following conception become cancerous); Hodgkin's lymphoma andlaryngeal cancer

In one embodiment, cancer comprises various types of leukemias such aschronic lymphocytic leukemia, chronic myelocytic leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia and acutemyeloblastic leukemia.

In some embodiments, acute leukemia includes, but is not limited toundifferentiated AML (M0), myeloblastic leukemia (M1), myeloblasticleukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]),myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]),monocytic leukemia (M5), erythroleukemia (M6), megakaryoblastic leukemia(M7). In some embodiments, acute lymphocytic leukemia (ALL) includesleukemia that originates in the blast cells of the bone marrow(B-cells), thymus (T-cells) and lymph nodes. The acute lymphocyticleukemia is categorized as L1—Mature-appearing lymphoblasts (T-cells orpre-B-cells), L2—Immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells) and L3—Lymphoblasts (B-cells;Burkitt's cells).

In one embodiment, cancer is cancer of stomach, gastric, bone, ovary,colon, lung, brain, larynx, lymphatic system, genitourinary tract,squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma,lung cancer, bladder cancer, head and neck cancer, melanoma, prostatecancer, breast cancer, small-cell lung cancer, leukemia, glioma,colorectal cancer, genitourinary cancer, gastrointestinal cancer,hematologic cancer or pancreatic cancer. In particular, acutemyelogenous leukemia (AML), B-precursor cell acute lymphoblasticleukemias, myelodysplastic leukemias, T-cell acute lymphoblasticleukemias and chronic myelogenous leukemias (CMLs).

The cancers to be treated herein may be primary or metastatic. In oneembodiment, the cancer is a solid or blood born metastatic tumor. Inanother embodiment, the cancer is metastatic cancer of bone.

B) Nonmalignant proliferation diseases; atherosclerosis, restenosisfollowing vascular angioplasty and fibroproliferative disorders such asobliterative bronchiolitis.

C) Inflammatory diseases or disorders related to immune dysfunction,including, immunodeficiency, immunomodulation, autoimmune diseases,tissue rejection, wound healing, kidney disease, allergies, inflammatorybowel disease, Lupus Erythematosis, arthritis, osteoarthritis,rheumatoid arthritis, asthma and rhinitis.

D) Infectious diseases mediated either via viral or bacterial pathogens.

Compositions and methods for treating a disease comprising administeringto a subject an effective amount of a Kit or stem cell factor receptor(SCFR) modulating compound are provided herein. In one embodiment, thedisease is cancer. In another embodiment, the disease is carcinoma. Insome embodiments, the cancer is small-cell lung cancer, or breastcancer. In another embodiment, the disease is prostate carcinoma. In yetanother embodiment, the cancer is endometrial cancer. In anotherembodiment, the cancer is glioma. In other embodiments, the cancer is amalignant tumor, or a hematologic malignancy such as leukemia andlymphoma. In some embodiments, the leukemia is acute myelogenousleukemia (AML). In some embodiment, the leukemia is mast cell leukemia.In another embodiment, the disease is systemic mastocytosis. In yetanother embodiment, the disease is myelodysplastic syndrome (MDS). Insome embodiments, the malignant tumor is a germ cell tumor. In anotherembodiment, the germ cell tumor is semiomas and/or dysgerminomas. In yetanother embodiment, the disease is gastrointestinal stromal tumor(GIST). In yet another embodiment, the disease is mast cell tumor, a,melanoma, or a neuroblastoma.

Compositions and methods for treating a disease comprising administeringto a subject in need thereof an effective amount of a Platelet-DerivedGrowth Factor (PDGF) receptor modulating compound are provided herein.In one embodiment, the disease is cancer. In another embodiment, thedisease is carcinoma. In another embodiment, the carcinoma is ovariancarcinoma. In yet another embodiment, the carcinoma is breast carcinoma.In another embodiment, the carcinoma is renal cell carcinoma. In yetanother embodiment, the disease is sarcoma. In other embodiments, thecancer is a malignant tumor, or a hematologic malignancy such asleukemia and lymphoma. In some embodiments, the leukemia is acutelymphoblastic leukemia (ALL). In another embodiment, the leukemia ischronic myelogenous leukemia (CML). In some embodiments, the lymphoma isT-cell lymphoma. In another embodiment, the disease is idiopathichypereosinophilic syndrome (HES). In another embodiment, the disease ischronic eosinophilic leukemia (CEL). In some embodiments, the malignanttumor is melanoma, or glioblastoma. In another embodiment, the diseaseis tumor angiogenesis. In a further embodiment, the disease is anonmalignant proliferation disease. In some embodiments, thenonmalignant proliferation disease is atherosclerosis, or restenosis. Ina still further embodiment, the disease is a fibroproliferativedisorder. In some embodiments, the fibroproliferative disorder isobliterative bronchiolitis. In another embodiment, thefibroproliferative disorder is idiopathic myelofibrosis.

Compositions and methods for treating a disease comprising administeringto a subject in need thereof an effective amount of a Flt-3 receptormodulating compound are provided herein. In one embodiment, the diseaseis cancer. In another embodiment, the disease is carcinoma. In someembodiments, the cancer is small-cell lung cancer, or breast cancer. Inother embodiments, the cancer is a malignant tumor, or a hematologicmalignancy such as leukemia and lymphoma. In another embodiment, thedisease is a hematologic malignance such as leukemia and/or lymphoma. Insome embodiments, the leukemia is acute myelogenous leukemia (AML) or ischronic myeloid leukemia (CML). In some embodiments, the cancer is acutelymphoblastic leukemia (ALL), myelodysplastic leukemia, T-cell acutelymphoblastic leukemia, and B-cell acute lymphoblastic leukemia. Inanother embodiment, the disorder is the myelodysplastic syndrome. In yetanother embodiment, the disease is an immune system disorder and/orinflammatory disease. In another embodiment, the immune system disorderis systemic lupus erythematosis. In another embodiment, the immunesystem disorder is inflammatory bowel disease. In another embodiment,the inflammatory bowel disease is Crohn's disease and/or ulcerativecolitis. In another embodiment, the immune system disorder is chronicobstructive pulmonary disease.

Compositions and methods for treating a disease comprising administeringto a subject in need thereof an effective amount of VEGFR-modulatingcompound are provided herein. In one embodiment, the disease is cancer.In another embodiment, the disease is carcinoma. In another embodiment,the disease is solid tumor. In another embodiment, the disease ismetastatic tumor. In another embodiment, the disease is stromal tumors.In yet another embodiment, the disease is neuroendocrine tumors. In yetanother embodiment, the disease or disorder is tumor angiogenesis. Inanother embodiment, the disease is sarcoma. In another embodiment, thesarcoma is Kaposi's sarcoma, hemangiosarcoma and/or lymphangiosarcoma.

Compositions and methods for treating a disease comprising administeringto a subject in need thereof an effective amount of CSF-1R- (or fms-)modulating compound are provided herein. In one embodiment, the diseaseis cancer. In another embodiment, the disease is carcinoma. In yetanother embodiment, the disease is metastatic tumor. In anotherembodiment, the metastatic tumor is metastases to the bone. In yetanother embodiment, the disease is Langerhans cell histiocytosis. In yetanother embodiment, the disease is an immune system disorder and/orinflammatory disease. In another embodiment, the immune system disorderis systemic lupus erythematosis. In another embodiment, the immunesystem disorder is inflammatory bowel disease. In another embodiment,the inflammatory bowel disease is Crohn's disease and/or ulcerativecolitis. In another embodiment, the immune system disorder is rheumatoidarthritis. In yet another embodiment, the immune system disorder ismultiple sclerosis. In yet another embodiment, the immune systemdisorder is systemic lupus erythematosis. In yet another embodiment, theimmune system disorder is allergic rhinitis and/or asthma. In anotherembodiment, the immune system disorder is type 1 diabetes.

Compositions and methods for treating a disease comprising administeringto a subject in need thereof an effective amount of Ret-modulatingcompound are provided herein. In one embodiment, the disease is cancer.In another embodiment, the disease is carcinoma. In yet anotherembodiment, the carcinoma is thyroid carcinoma. In yet anotherembodiment, the thyroid carcinoma is sporadic or familial medullarycarcinoma. In another embodiment, the thyroid carcinoma is papillarythyroid carcinoma. In yet another embodiment, the thyroid carcinoma isparathyroid carcinoma. In another embodiment, the disease is multipleendocrine neoplasia 2A or 2B.

Also contemplated herein are combination therapies using one or morecompounds or compositions provided herein, or pharmaceuticallyacceptable derivatives thereof, in combination with otherpharmaceutically active agents for the treatment of the diseases anddisorders described herein.

In one embodiment, such additional pharmaceutical agents include one ormore of the following; anti-cancer agents, and anti-inflammatory agents.

The compound or composition provided herein, or pharmaceuticallyacceptable derivative thereof, may be administered simultaneously with,prior to, or after administration of one or more of the above agents.Pharmaceutical compositions containing a compound provided herein andone or more of the above agents are also provided.

In practicing the methods, effective amounts of the compounds orcompositions containing therapeutically effective concentrations of thecompounds, which are formulated for systemic delivery, includingparenteral, oral, or intravenous delivery, or for local or topicalapplication are administered to an individual exhibiting the symptoms ofthe disease or disorder to be treated. The amounts are effective toameliorate or eliminate one or more symptoms of the diseases ordisorders.

Also contemplated herein are combination therapies using one or morecompounds or compositions provided herein, or pharmaceuticallyacceptable salts thereof, in combination with other pharmaceuticallyactive agents for the treatment of the diseases and disorders describedherein.

In one embodiment, such additional pharmaceutical agents include one ormore of the following; anti-cancer agents and anti-inflammatory agents.

The compound or composition provided herein, or pharmaceuticallyacceptable salt, solvate, hydrate or prodrug thereof, may beadministered simultaneously with, prior to, or after administration ofone or more of the above agents. Pharmaceutical compositions containinga compound provided herein and one or more of the above agents are alsoprovided.

In practicing the methods, effective amounts of the compounds orcompositions containing therapeutically effective concentrations of thecompounds, which are formulated for oral, systemic, including parenteralor intravenous delivery, or for local or topical application areadministered to an individual exhibiting the symptoms of the disease ordisorder to be treated. The amounts are effective to treat, manage orameliorate the disease or ameliorate or eliminate one or more symptomsof the disease or disorder.

Further provided is a pharmaceutical pack or kit comprising one or morecontainers filled with one or more of the ingredients of thepharmaceutical compositions. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use of sale for human administration. The pack or kit canbe labeled with information regarding mode of administration, sequenceof drug administration (e.g., separately, sequentially or concurrently),or the like.

These and other aspects of the subject matter described herein willbecome evident upon reference to the following detailed description.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 depicts results of tumor growth delay experiment in a MV4-11human leukemia xenograft model. A compound provided herein wasadministered by oral gavage (p.o.) once daily for twenty-eight days(qd×28) to mice implanted with MV4-11 tumors. The compound at 3 mg/kgand 10 mg/kg inhibits growth of MV4-11 xenographs in a statisticallysignificant manner (p<0.01) compared to vehicle controls in the absenceof morbidity or mortality.

DETAILED DESCRIPTION

Provided herein are imidazolothiazole compounds of formula (I) that haveactivity as protein kinase modulators. Further provided are methods oftreating, preventing or ameliorating diseases that are modulated byprotein kinases and pharmaceutical compositions and dosage forms usefulfor such methods. The methods and compositions are described in detailin the sections below.

A. DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond, e.g., methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), and the like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond or a double bond, e.g.,ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and thelike.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onetriple bond, having from two to ten carbon atoms, and which is attachedto the rest of the molecule by a single bond or a triple bond, e.g.,ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl and the like.

“Alkylene” and “alkylene chain” refer to a straight or branched divalenthydrocarbon chain consisting solely of carbon and hydrogen, containingno unsaturation and having from one to eight carbon atoms, e.g.,methylene, ethylene, propylene, n-butylene and the like. The alkylenechain may be attached to the rest of the molecule through any twocarbons within the chain.

“Alkenylene” or “alkenylene chain” refers to a straight or branchedchain unsaturated divalent radical consisting solely of carbon andhydrogen atoms, having from one to eight carbon atoms, wherein theunsaturation is present only as double bonds and wherein the double bondcan exist between any two carbon atoms in the chain, e.g., ethenylene,prop-1-enylene, but-2-enylene and the like. The alkenylene chain may beattached to the rest of the molecule through any two carbons within thechain.

“Alkoxy” refers to the radical having the formula —OR wherein R is alkylor haloalkyl. An “optionally substituted alkoxy” refers to the radicalhaving the formula —OR wherein R is an optionally substituted alkyl asdefined herein.

“Alkynylene” or “alkynylene chain” refers to a straight or branchedchain unsaturated divalent radical consisting solely of carbon andhydrogen atoms, having from one to eight carbon atoms, wherein theunsaturation is present only as triple bonds and wherein the triple bondcan exist between any two carbon atoms in the chain, e.g., ethynylene,prop-1-ynylene, but-2-ynylene, pent-1-ynylene, pent-3-ynylene and thelike. The alkynylene chain may be attached to the rest of the moleculethrough any two carbons within the chain.

“Amino” refers to a radical having the formula —NR′R″ wherein R′ and R″are each independently hydrogen, alkyl or haloalkyl. An “optionallysubstituted amino” refers to a radical having the formula —NR′R″ whereinone or both of R′ and R″ are optionally substituted alkyl as definedherein.

“Anti-cancer agents” refers to anti-metabolites (e.g., 5-fluoro-uracil,methotrexate, fludarabine), antimicrotubule agents (e.g., vincaalkaloids such as vincristine, vinblastine; taxanes such as paclitaxel,docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan,carmustine, nitrosoureas such as bischloroethylnitrosurea andhydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin,JM-216, CI-973), anthracyclines (e.g., doxorubicin, daunorubicin),antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin,daunomycin), topoisomerase inhibitors (e.g., etoposide, camptothecins),anti-angiogenesis agents (e.g. Sutent® and Bevacizumab) or any othercytotoxic agents, (estramustine phosphate, prednimustine), hormones orhormone agonists, antagonists, partial agonists or partial antagonists,kinase inhibitors, and radiation treatment.

“Anti-inflammatory agents” refers to matrix metalloproteinaseinhibitors, inhibitors of pro-inflammatory cytokines (e.g., anti-TNFmolecules, TNF soluble receptors, and IL1) non-steroidalanti-inflammatory drugs (NSAIDs) such as prostaglandin synthaseinhibitors (e.g., choline magnesium salicylate, salicylsalicyclic acid),COX-1 or COX-2 inhibitors), or glucocorticoid receptor agonists such ascorticosteroids, methylprednisone, prednisone, or cortisone.

“Aryl” refers to a radical of carbocylic ring system wherein at leastone of the rings is aromatic. The aryl may be fully aromatic, examplesof which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl,fluorenyl, indenyl and pyrenyl. The aryl may also contain an aromaticring in combination with a non-aromatic ring, examples of which areacenaphene, indene, and fluorene.

“Aralkyl” refers to a radical of the formula —R_(a)R_(b) where R_(a) isan alkyl radical as defined above, substituted by R_(b), an arylradical, as defined above, e.g., benzyl. Both the alkyl and arylradicals may be optionally substituted as defined herein.

“Aralkoxy” refers to a radical of the formula —OR_(a)R_(b) where—R_(a)R_(b) is an aralkyl radical as defined above. Both the alkyl andaryl radicals may be optionally substituted as defined herein.

“Cycloalkyl” refers to a stable monovalent monocyclic or bicyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,having from three to ten carbon atoms, and which is saturated andattached to the rest of the molecule by a single bond, e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane,norbornene, adamantyl, bicyclo[2.2.2]octane and the like.

“Cycloalkylalkyl” refers to a radical of the formula —R_(a)R_(d) whereR_(a) is an alkyl radical as defined above and R_(d) is a cycloalkylradical as defined above. The alkyl radical and the cylcoalkyl radicalmay be optionally substituted as defined herein.

“Halo”, “halogen” or “halide” refers to F, Cl, Br or I.

“Haloalkyl” refers to an alkyl group in which one or more of thehydrogen atoms are replaced by halogen. Such groups include, but are notlimited to, chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.

“Haloalkenyl” refers to an alkenyl group in which one or more of thehydrogen atoms are replaced by halogen. Such groups include, but are notlimited to, 1-chloro-2-fluoroethenyl.

“Heterocyclyl” refers to a stable 3- to 15-membered ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur. In one embodiment,the heterocyclic ring system radical may be a monocyclic, bicyclic ortricyclic ring or tetracyclic ring system, which may include fused orbridged ring systems; and the nitrogen or sulfur atoms in theheterocyclic ring system radical may be optionally oxidized; thenitrogen atom may be optionally quaternized; and the heterocyclylradical may be partially or fully saturated or aromatic. Theheterocyclic ring system may be attached to the main structure at anyheteroatom or carbon atom which results in the creation of a stablecompound. Examples of such heterocyclic radicals include, but are notlimited to: acridinyl, azepinyl, benzimidazolyl, benzindolyl,benzisoxazinyl, benzo[4,6]imidazo[1,2-a]pyridinyl, benzodioxanyl,benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl,benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiadiazolyl, benzothiazolyl,benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl,benzoxazolyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromanyl,chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dibenzofuranyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl,dihydrofuryl, dihydropyranyl, dioxolanyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl,dioxolanyl, 1,4-dithianyl, furanonyl, furanyl, imidazolidinyl,imidazolinyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl,indolinyl, indolizinyl, indolyl, isobenzotetrahydrofuranyl,isobenzotetrahydrothienyl, isobenzothienyl, isochromanyl, isocoumarinyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl,isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroindolyl, octahydroisoindolyl, oxadiazolyl, oxazolidinonyl,oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl, perimidinyl,phenanthridinyl, phenathrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,4-piperidonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl,pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl,tetrazolyl, thiadiazolopyrimidinyl, thiadiazolyl, thiamorpholinyl,thiazolidinyl, thiazolyl, thiophenyl, triazinyl, triazolyl and1,3,5-trithianyl.

“Heteroaralkyl” refers to a radical of the formula —R_(a)R_(f) whereR_(a) is an alkyl radical as defined above and R_(f) is a heteroarylradical as defined herein. The alkyl radical and the heteroaryl radicalmay be optionally substituted as defined herein.

“Heteroaralkoxy” refers to a radical of the formula —OR_(a)R_(f) where—R_(a)R_(f) is a heteroaralkyl radical as defined above. The alkylradical and the heteroaryl radical may be optionally substituted asdefined herein.

“Heteroaryl” refers to a heterocyclyl radical as defined above which isaromatic. The heteroaryl radical may be attached to the main structureat any heteroatom or carbon atom which results in the creation of astable compound. Examples of such heteroaryl radicals include, but arenot limited to: acridinyl, benzimidazolyl, benzindolyl, benzisoxazinyl,benzo[4,6]imidazo[1,2-a]pyridinyl, benzofuranyl, benzonaphthofuranyl,benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl,benzothiopyranyl, benzoxazinyl, benzoxazolyl, benzothiazolyl,β-carbolinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl,imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolizinyl,indolyl, isobenzothienyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, naphthyridinyl, octahydroindolyl, octahydroisoindolyl,oxazolidinonyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl,perimidinyl, phenanthridinyl, phenathrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazinyl andtriazolyl.

“Heterocyclylalkyl” refers to a radical of the formula —R_(a)R_(e)wherein R_(a) is an alkyl radical as defined above and R_(e) is aheterocyclyl radical as defined herein. The alkyl radical and theheterocyclyl radical may be optionally substituted as defined herein.

“Heterocyclylalkoxy” refers to a radical of the formula —OR_(a)R_(e)wherein —R_(a)R_(e) is a heterocyclylalkyl radical as defined above. Thealkyl radical and the heterocyclyl radical may be optionally substitutedas defined herein.

“IC₅₀” refers to an amount, concentration or dosage of a particular testcompound that achieves a 50% inhibition of a maximal response, such ascell growth or proliferation measured via any the in vitro or cell basedassay described herein.

“Optionally substituted alkyl”, “optionally substituted alkenyl” and“optionally” refer to alkyl radicals, alkenyl radicals and alkynylradicals, respectively, substituted alkynyl that may be optionallysubstituted by one or more substituents independently selected from thegroup consisting of nitro, halo, azido, cyano, cycloalkyl, heteroaryl,heterocyclyl, —OR^(x), —N(R^(y))(R^(z)), —SR^(x), —C(J)R^(x),—C(J)OR^(x), —C(J)N(R^(y))(R^(z)), —C(J)SR^(x), —S(O)_(t)R^(w) (where tis 1 or 2), —OC(J)R^(x), —OC(J)OR^(x), —OC(J)N(R^(y))(R^(z)),—OC(J)SR^(x), —N(R^(x))C(J)R^(x), —N(R^(x))C(J)OR^(x),—N(R^(x))C(J)N(R^(y))(R^(z)), —N(R^(x))C(J)SR^(x), —Si(R^(w))₃,—N(R^(x))S(O)₂R^(w), —N(R^(x))S(O)₂N(R^(y))(R^(z)),—S(O)₂N(R^(y))(R^(z)), —P(O)(R^(v))₂, —OP(O)(R^(v))₂,—C(J)N(R^(x))S(O)₂R^(w), —C(J)N(R^(x))N(R^(x))S(O)₂R^(w),—C(R^(x))═N(OR^(x)), and —C(R^(x))═NN(R^(y))(R^(z)), wherein:

R^(x) is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl; or

R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocyclyl or heteroaryl;

R^(w) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

R^(v) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, hydroxy, —OR^(x) or —N(R^(y))(R^(z)); and J is O, NR^(x)or S.

Unless stated otherwise specifically described in the specification, itis understood that the substitution can occur on any carbon of thealkyl, alkenyl or alkynyl group.

“Optionally substituted aryl”, “optionally substituted cycloalkyl”,“optionally substituted heteroaryl” and “optionally substitutedheterocyclyl” refers to aryl, cycloalkyl, heterocyclyl and heteroarylradicals, respectively, that are optionally substituted by one or moresubstituents selected from the group consisting of nitro, halo,haloalkyl, haloalkenyl, azido, cyano, oxo, thioxo, imino, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, heteroaralkyl, —R^(u)OR^(x),—R^(u)N(R^(y))(R^(z)), —R^(u)SR^(x), —R^(u)C(J)R^(x), —R^(u)C(J)OR^(x),—R^(u)C(J)N(R^(y))(R^(z)), —R^(u)C(J)SR^(x), —R^(u)S(O)_(t)R^(w) (wheret is 1 or 2), —R^(u)OC(J)R^(x), —R^(u)OC(J)OR^(x),—R^(u)OC(J)N(R^(y))(R^(z)), —R^(u)OC(J)SR^(x), —R^(u)N(R^(x))C(J)R^(x),—R^(u)N(R^(x))C(J)OR^(x), —R^(u)N(R^(x))C(J)N(R^(y))(R^(z)),—R^(u)N(R^(x))C(J)SR^(x), —R^(u)Si(R^(w))₃, —R^(u)N(R^(x))S(O)₂R^(w),—R^(u)N(R^(x))S(O)₂N(R^(y))(R^(z)), —R^(u)S(O)₂N(R^(y))(R^(z)),—R^(u)P(O)(R^(v))₂, —R^(u)OP(O)(R^(v))₂, —R^(u)C(J)N(R^(x))S(O)₂R^(w),—R^(u)C(J)N(R^(x))N(R^(x))S(O)₂R^(w), —R^(u)C(R^(x))═N(OR^(x)) and—R^(u)C(R^(x))═NN(R^(y))(R^(z)), wherein:

each R^(u) is independently alkylene or a direct bond;

each R^(v) is independently alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, hydroxy, —OR^(x) or —N(R^(y))(R^(z));

R^(w) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, orheteroaralkyl;

each R^(x) is independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl,aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,aryl, aralkyl, heteroaryl, or heteroaralkyl;

R^(y) and R^(z), together with the nitrogen atom to which they areattached, form a heterocycle or heteroaryl; and

J is O, NR^(x) or S.

Unless stated otherwise specifically described in the specification, itis understood that the substitution can occur on any atom of thecycloalkyl, heterocyclyl, aryl or heteroaryl group.

“Oxo” refers to ═O.

“Pharmaceutically acceptable derivatives” of a compound include salts,esters, enol ethers, enol esters, acetals, ketals, orthoesters,hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugsthereof. Such derivatives may be readily prepared by those of skill inthis art using known methods for such derivatization. The compoundsproduced may be administered to animals or humans without substantialtoxic effects and either are pharmaceutically active or are prodrugs.

Pharmaceutically acceptable salts include, but are not limited to, aminesalts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates.

Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl and heterocyclyl esters of acidic groups, including, but notlimited to, carboxylic acids, phosphoric acids, phosphinic acids,sulfonic acids, sulfinic acids and boronic acids.

Pharmaceutically acceptable enol ethers include, but are not limited to,derivatives of formula C═C(OR) where R is hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl orheterocyclyl. Pharmaceutically acceptable enol esters include, but arenot limited to, derivatives of formula C═C(OC(O)R) where R is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl or heterocyclyl.

As used herein and unless otherwise indicated, the term “hydrate” meansa compound provided herein or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

As used herein and unless otherwise indicated, the term “solvate” meansa solvate formed from the association of one or more solvent moleculesto a compound provided herein. The term “solvate” includes hydrates(e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like).

“Prodrug” is a compound that, upon in vivo administration, ismetabolized by one or more steps or processes or otherwise converted tothe biologically, pharmaceutically or therapeutically active form of thecompound. To produce a prodrug, the pharmaceutically active compound ismodified such that the active compound will be regenerated by metabolicprocesses. The prodrug may be designed to alter the metabolic stabilityor the transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound (see, e.g., Nogrady (2005) Medicinal ChemistryA Biochemical Approach, Oxford University Press, New York).

“Sulfide” refers to the radical having the formula —SR wherein R is analkyl or haloalkyl group. An “optionally substituted sulfide” refers tothe radical having the formula —SR wherein R is an optionallysubstituted alkyl as defined herein.

As used herein, “substantially pure” means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Methods for purification ofthe compounds to produce substantially chemically pure compounds areknown to those of skill in the art. A substantially chemically purecompound may, however, be a mixture of stereoisomers. In such instances,further purification might increase the specific activity of thecompound.

Unless specifically stated otherwise, where a compound may assumealternative tautomeric, regioisomeric and/or stereoisomeric forms, allalternative isomers are intended to be encompassed within the scope ofthe claimed subject matter. For example, where a compound is describedas having one of two tautomeric forms, it is intended that the bothtautomers be encompassed herein.

Thus, the compounds provided herein may be enantiomerically pure, or bestereoisomeric or diastereomeric mixtures. In the case of amino acidresidues, such residues may be of either the L- or D-form. Theconfiguration for naturally occurring amino acid residues is generallyL. When not specified the residue is the L form. As used herein, theterm “amino acid” refers to α-amino acids which are racemic, or ofeither the D- or L-configuration. The designation “d” preceding an aminoacid designation (e.g., dAla, dSer, dVal, etc.) refers to the D-isomerof the amino acid. The designation “dI” preceding an amino aciddesignation (e.g., dIPip) refers to a mixture of the L- and D-isomers ofthe amino acid. It is to be understood that the chiral centers of thecompounds provided herein may undergo epimerization in vivo. As such,one of skill in the art will recognize that administration of a compoundin its (R) form is equivalent, for compounds that undergo epimerizationin vivo, to administration of the compound in its (S) form.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof.

Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers maybe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, such as reverse phase HPLC.

As used herein, the term “enantiomerically pure” or “pure enantiomer”denotes that the compound comprises more than 75% by weight, more than80% by weight, more than 85% by weight, more than 90% by weight, morethan 91% by weight, more than 92% by weight, more than 93% by weight,more than 94% by weight, more than 95% by weight, more than 96% byweight, more than 97% by weight, more than 98% by weight, more than98.5% by weight, more than 99% by weight, more than 99.2% by weight,more than 99.5% by weight, more than 99.6% by weight, more than 99.7% byweight, more than 99.8% by weight or more than 99.9% by weight, of theenantiomer.

Where the number of any given substituent is not specified (e.g.,haloalkyl), there may be one or more substituents present. For example,“haloalkyl” may include one or more of the same or different halogens.

In the description herein, if there is any discrepancy between achemical name and chemical structure, the structure preferably controls.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, Biochem. 1972, 11:942-944).

B. COMPOUNDS

In one embodiment, the compounds provided are of formula (I):

wherein,

bond b is a single bond or double bond;

X is —S—, —N(R⁵)— or —O—;

Z¹ and Z³ are each independently —N(R⁵)—, —(CH₂)_(q), —O—, —S—, or adirect bond;

Z² is —C(O)— or —C(S)—;

m is an integer from 1 to 2;

n is an integer from 1 to 3;

each q is independently an integer from 1 to 4;

R⁰ is hydrogen, halo, hydroxy, optionally substituted alkyl, oroptionally substituted alkoxy;

each R¹ is independently selected from the group consisting of halo,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheteroaralkyl, optionally substituted heteroaralkenyl, —R⁶OR⁷, —R⁶SR⁷,—R⁶S(O)_(t)R⁸ (where t is 1 or 2), —R⁶N(R⁷)₂, —R⁶CN, —R⁶C(O)R⁷,—R⁶C(S)R⁷, —R⁶C(NR⁷)R⁷, —R⁶C(O)OR⁷, —R⁶C(S)OR⁷, —R⁶C(NR⁷)OR⁷,—R⁶C(O)N(R⁷)₂, —R⁶C(S)N(R⁷)₂, —R⁶C(NR⁷)N(R⁷)₂, —R⁶C(O)N(R⁷)R⁹N(R⁷)₂,—R⁶C(O)SR⁸, —R⁶C(S)SR⁸, —R⁶C(NR⁷)SR⁸, —R⁶S(O)_(t)OR⁷ (where t is 1 or2), —R⁶S(O)_(t)N(R⁷)₂ (where t is 1 or 2), —R⁶S(O)_(t)N(R⁷)N(R⁷)₂ (wheret is 1 or 2), —R⁶S(O)_(t)N(R⁷)N═C(R⁷)₂, —R⁶S(O)_(t)N(R⁷)C(O)R⁸ (where tis 1 or 2), —R⁶S(O)_(t)N(R⁷)C(O)N(R⁷)₂ (where t is 1 or 2),—R⁶S(O)_(t)N(R⁷)C(NR⁷)N(R⁷)₂ (where t is 1 or 2), —R⁶N(R⁷)C(O)R⁸,—R⁶N(R⁷)C(O)OR⁸, —R⁶N(R⁷)C(O)SR⁸, —R⁶N(R⁷)C(NR⁷)SR⁸, —R⁶N(R⁷)C(S)SR⁸,—R⁶N(R⁷)C(O)N(R⁷)₂, —R⁶N(R⁷)C(NR⁷)N(R⁷)₂, —R⁶N(R⁷)C(S)N(R⁷)₂,—R⁶N(R⁷)S(O)_(t)R⁸ (where t is 1 or 2), —R⁶OC(O)R⁸, —R⁶OC(NR⁷)R⁸,—R⁶OC(S)R⁸, —R⁶OC(O)OR⁸, —R⁶OC(NR⁷)OR⁸, —R⁶OC(S)OR⁸, —R⁶OC(O)SR⁸,—R⁶OC(O)N(R⁷)₂, —R⁶OC(NR⁷)N(R⁷)₂, —R⁶OC(S)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂,—R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)R⁹C(O)R⁷, —R⁶C(O)R⁹C(S)R⁷,—R⁶C(O)R⁹C(NR⁷)R⁷, —R⁶C(O)R⁹C(O)OR⁷, —R⁶C(O)R⁹C(S)OR⁷,—R⁶C(O)R⁹C(NR⁷)OR⁷, —R⁶C(O)R⁹C(O)N(R⁷)₂, —R⁶C(O)R⁹C(S)N(R⁷)₂,—R⁶C(O)R⁹C(NR⁷)N(R⁷)₂, —R⁶C(O)R⁹C(O)SR⁸, —R⁶C(O)R⁹C(S)SR⁸ and—R⁶C(O)R⁹C(NR⁷)SR⁸;

each R² is independently selected from hydrogen, halo, nitro, cyano,optionally substituted alkyl, —OR¹², —SR¹², —N(R¹²)₂, —S(O)_(t)R¹³(where t is 1 or 2), —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², or—N(R¹²)S(O)_(t)R¹³ (where t is 1 or 2);

R³ is hydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR¹²,—SR¹², —N(R¹²)₂, —S(O)_(t)R¹³ (where t is 1 or 2), —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —C(O)SR¹², or —N(R¹²)S(O)_(t)R¹³ (where t is 1 or 2);

R⁴ is selected from the group consisting of optionally substitutedalkyl, optionally substituted heterocyclyl, optionally substitutedheteroaryl, optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, and optionally substituted aryl;

each R⁵ is independently hydrogen, or optionally substituted alkyl;

each R⁶ is independently a direct bond, an optionally substitutedstraight or branched alkylene chain, or an optionally substitutedstraight or branched alkenylene chain;

each R⁷ is independently selected from (i) or (ii) below

(i) R⁷ is selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl, or

(ii) two (R⁷)s together with the atom to which they are attached form anoptionally substituted heterocyclyl or optionally substitutedheteroaryl;

R⁸ is independently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl;

each R⁹ is independently an optionally substituted straight or branchedalkylene chain or an optionally substituted straight or branchedalkenylene chain;

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroaralkyl; and

R¹³ is independently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl;

with the proviso that,

(i) if -Z¹Z²Z³R⁴ is —NHC(O)Bu then R¹ may not be ethoxy;

(ii) if -Z¹Z²Z³R⁴ is —C(O)OR_(p), where R_(p)=H, methyl, or ethyl, thenR¹ may not be hydroxyl, methoxy or methoxycarbonyl;

(iii) if -Z¹Z²Z³R⁴ is —NHC(O)C(O)OR_(p), where R_(p)=H, methyl, orethyl, then R¹ may not be methoxy;

(iv) if -Z¹Z²Z³R⁴ is —CH₂C(O)OR_(p), where R_(p)=H, methyl, or ethyl,then R¹ may not be methoxy or ethoxy;

(v) if -Z¹Z²Z³R⁴ is —OC(O)CH₃, then R¹ may not be methyl, methoxy orethoxy.

In one embodiment, the compound is a single isomer, a mixture ofisomers, a racemic mixture of isomers, a solvate, a hydrate or aprodrug; or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound provided herein is a pharmaceuticallyacceptable salt of the compound of formula (I). In one embodiment, thecompounds provided herein is a solvate of the compound of formula (I).In one embodiment, the compounds provided herein is a hydrate ofcompound of formula (I). In one embodiment, the compound provided hereinis a prodrug of the compound of formula (I).

In one embodiment, the -Z¹Z²Z³R⁴ group is attached at a para position onthe phenyl ring. In one embodiment, the -Z¹Z²Z³R⁴ group is attached at ameta position on the phenyl ring.

In one embodiment, R⁴ is optionally substituted heterocyclyl oroptionally substituted heteroaryl and other variables are as describedelsewhere herein. The substituents on R⁴, when present, are selectedfrom one or more, in one embodiment, one, two, three or four groupsselected from halo, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheterocyclyl, and optionally substituted heteroaryl. In one embodiment,R⁴ is 3-12 membered optionally substituted heterocyclyl, wherein thehetero atoms are selected from one or more nitrogen, sulfur or oxygen.In one embodiment, R⁴ is 5-10 membered optionally substitutedheterocyclyl. In one embodiment, R⁴ is 5-12 membered optionallysubstituted heteroaryl, wherein the hetero atoms are selected from oneor more nitrogen, sulfur or oxygen. In one embodiment, R⁴ is 5-6membered optionally substituted heteroaryl.

In another embodiment, R⁴ is selected from the group consisting of:

wherein, each R¹⁰ is independently selected from hydrogen, halo,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heterocyclyl, andoptionally substituted heteroaryl.

In another embodiment, R⁴ is selected from the group consisting of:

and each R¹⁰ is independently selected from hydrogen, halo, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, and optionallysubstituted heteroaryl.

In another embodiment, the compounds provided herein have formula (I),wherein R⁴ is selected from the group consisting of:

and each R¹⁰ is independently selected from hydrogen, halo, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, and optionallysubstituted heteroaryl. In one embodiment, R¹⁰ is hydrogen, alkyl,haloalkyl or haloaryl. In one embodiment, R¹⁰ is hydrogen, methyl,tert-butyl, trifluoromethyl or p-chlorophenyl. In one embodiment, R¹⁰ istert-butyl.

In one embodiment, R⁴ is

where R¹⁰ is as described elsewhere herein. In one embodiment, R¹⁰ isalkyl. In one embodiment, R¹⁰ is hydrogen. In one embodiment, one R¹⁰ isalkyl and the other R¹⁰ is hydrogen.

In one embodiment, R⁴ is

In another embodiment, R¹ is —R⁶OR⁹N(R⁷)₂, wherein R⁶ is a direct bond,an optionally substituted straight or branched alkylene chain or anoptionally substituted straight or branched alkenylene chain;

two (R⁷)s together with the nitrogen atom to which they are attachedform an optionally substituted heterocyclyl or optionally substitutedheteroaryl; and

R⁹ is an optionally substituted straight or branched alkylene chain oran optionally substituted straight or branched alkenylene chain.

In another embodiment, R¹ is

where K is —C(O)—, —(CH₂)_(q)—, —(CH₂)_(q)O—, —(CH₂)_(q)—, —(CH₂)_(q)—,—(CH₂)_(q)C(O)—, —C(O)NH(CH₂)_(q)—, —C(O)NH(CH₂)_(q)NH(CH₂)_(q)—,—(CH₂)_(q)C(O)NH(CH₂)_(q)—, —O(CH₂)_(q)—, —OC(O)—, —OC(O)(CH₂)_(q)— or adirect bond;

Y is —O—, —S—, —S(O)—, —S(O)₂—, —N(R¹⁴)—, —C(H)R¹⁵—, or —C(O)—;

p is an integer from 0 to 2;

each q is independently an integer from 1 to 4;

R¹⁴ is hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heteroaryl, optionally substitutedaryl, S(O)_(t)R¹³ (where t is 1 or 2), —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, or —C(O)SR¹²;

R¹⁵ is hydrogen, halo, nitro, cyano, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted heteroaryl,optionally substituted aryl, —OR¹², —SR¹², —N(R¹²)₂, —S(O)_(t)R¹³ (wheret is 1 or 2), —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², or—N(R¹²)S(O)_(t)R¹³ (where t is 1 or 2);

each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroaralkyl; and

each R¹³ is independently selected from the group consisting ofoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl.

In another embodiment, R¹ is halo, alkyl, —R⁶OR⁷, —R⁶N(R⁷)₂, —R⁶C(O)OR⁷,—R⁶OR⁹OR⁷, —R⁶OR⁹N(R⁷)₂, —R⁶C(O)N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)R⁹N(R⁷)R⁹OR⁷ or—R⁶C(O)N(R⁷)R⁹OR⁷ and R⁷ is hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroaralkyl.

In one embodiment, R¹ is fluoro, bromo, methyl, ethyl, hydroxy, methoxy,diethylamino or carboxy.

In one embodiment, q is 1-3. In one embodiment, q is 1, 2, 3 or 4. Inone embodiment, K is a direct bond.

In one embodiment, X is —S—. In another embodiment, X is —N(R⁵)—, whereR⁵ is hydrogen or lower alkyl. In another embodiment, X is —O—.

In one embodiment, -Z¹Z²Z³- is —NHC(O)NH—, —NHC(O)N(CH₃)—,—N(CH₃)C(O)NH—, —C(O)NH—, —NHC(O)—, —NCH₂C(O)NH—. In one embodiment,-Z¹Z²Z³- is —NHC(O)NH—.

In another aspect, provided herein is a compound of formula (Ia):

wherein the variables are as defined elsewhere herein.

In another aspect, provided herein is a compound of formula (Ia):

wherein the variables are as defined elsewhere herein.

In another aspect, provided herein is a compound of formula (II):

wherein

X is —S—, —N(R⁵)— or —O—;

X¹, X², X³, X⁴ are each independently selected from —C(R¹⁰)—, —C(R¹⁰)₂—,—N—, —N(R¹⁶)—, —O—, and —S—, provided that no more than two of X¹, X²,X³ and X⁴ are heteroatoms and wherein no two adjacent X's are both —O—or —S—;

and each R¹⁰ is independently selected from hydrogen, halo, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, and optionallysubstituted heteroaryl;

each R¹⁶ is independently selected from hydrogen, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heterocyclyl, and optionally substitutedheteroaryl; and

n, R⁰, R¹, R², R³, are defined as described above for formula (I);

as a single isomer, a mixture of isomers, a racemic mixture of isomers;a solvate, a hydrate or a prodrug; or as a pharmaceutically acceptablesalt thereof.

In one embodiment, the compounds provided herein have formula (II),wherein n is 0-3. In one embodiment, the compounds provided herein haveformula (II), wherein n is 0-3.

In another embodiment, the compound provided herein has formula (II)wherein R² and R³ are independently selected from hydrogen, halo oroptionally substituted lower alkyl.

In another aspect, provided herein is a compound of formula (III):

wherein:

X is —S—, —N(R⁵)— or —O—;

X¹ is —C(R¹⁰)—, or —N—;

X² is —O— or —S—;

where each R¹⁰ is independently selected from hydrogen, halo, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl, and optionallysubstituted heteroaryl;

and the remainder of n, R⁰, R¹, R², R³, R⁵ and X are as defined abovefor formula (I);

as a single isomer, a mixture of isomers, a racemic mixture of isomers,a solvate, a hydrate or a prodrug, or as a pharmaceutically acceptablesalt thereof.

In another aspect, provided herein is compound of formula (IIIa):

wherein the variables are as described elsewhere herein.

In another embodiment, compounds provided herein have formula (III)wherein X¹ is —N— and X² is —O—.

In another embodiment, compounds provided herein have formula (III)wherein R² and R³ are independently selected from hydrogen, halo oroptionally substituted lower alkyl.

In another aspect, the compound is of formula (III) wherein:

each R² is independently selected from hydrogen, halo, nitro, cyano,optionally substituted alkyl, —OR¹², —SR¹², —N(R¹²)₂, —S(O)_(t)R¹³(where t is 1 or 2), —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², or—N(R¹²)S(O)_(t)R¹³ (where t is 1 or 2);

each R³ is independently selected from hydrogen, halo, nitro, cyano,optionally substituted alkyl;

In one embodiment, the compounds provided herein have formula (II),wherein n is 0-3. In one embodiment, the compounds provided herein haveformula (II), wherein n is 0.

In another aspect, provided herein is a compound of formula (IV):

wherein:

K is —(CH₂)_(q)—, —(CH₂)_(q)O—, —(CH₂)_(q)O(CH₂)_(q)—, —(CH₂)_(q)C(O)—,—(CH₂)_(q)C(O)NH(CH₂)_(q)—, —O(CH₂)_(q)—, —OC(O)—, —OC(O)(CH₂)_(q)— or adirect bond;

X is —S—, —N(R⁵)— or —O—;

X¹ is —C(R¹⁰)—, or —N—;

X² is —O— or —S—;

Y is —O—, —S—, —S(O)—, —S(O)₂—, —N(R¹⁴)—, —C(H)R¹⁵—, or —C(O)—;

p is an integer from 0 to 2;

each q is independently an integer from 1 to 4;

R¹⁰ is independently selected from hydrogen, halo, optionallysubstituted alkyl, optionally substituted cycloalkyl, or optionallysubstituted aryl;

R¹⁴ is independently, hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted aryl, S(O)_(t)R¹³ (where t is 1 or 2), —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, or —C(O)SR¹²;

R¹⁵ is independently, hydrogen, halo, nitro, cyano, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted aryl, —OR¹², —SR¹²,—N(R¹²)₂, S(O)_(t)R¹³ (where t is 1 or 2), —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —C(O)SR¹², or —N(R¹²)S(O)_(t)R¹³ (where t is 1 or 2);

and the remainder of R⁰, R², R³, R⁵, R¹², R¹³ and X are as defined abovefor formula (I);

as a single isomer, a mixture of isomers, or as a racemic mixture ofisomers, or as a solvate, or as a prodrug, or as a pharmaceuticallyacceptable salt thereof.

In one embodiment, R¹⁴ is alkyl or —S(O)_(t)R¹³ where t is 1 or 2 andR¹³ is alkyl. In one embodiment, R¹⁴ is methyl, ethyl or —S(O)_(t)R¹³where t is 2 and R¹³ is methyl.

In another embodiment, compounds provided herein have formula (IV)wherein X¹ is —N— and X² is —O—.

In another embodiment, compounds provided herein have formula (IV)wherein R² and R³ are independently selected from hydrogen, halo oroptionally substituted lower alkyl.

In another embodiment, compounds provided herein have formula (IV)wherein R² and R³ are both hydrogen.

In another aspect, provided herein is a compound of formula (IVa):

or a single isomer, a mixture of isomers, a racemic mixture of isomers,a solvate, a prodrug, or as a pharmaceutically acceptable salt thereof,and the variables are as defined elsewhere herein.

In another aspect, provided herein is a compound of formula (IVb):

or a single isomer, a mixture of isomers, a racemic mixture of isomers,a solvate, a prodrug, or as a pharmaceutically acceptable salt thereof,where the variables are as defined elsewhere herein.

In another aspect, the compound provided herein is of formula (V):

wherein K is —O(CH₂)_(q)—, —(CH₂)_(q)O—, —(CH₂)_(q)O(CH₂)_(q)— or—(CH₂)_(q)—;

p is an integer from 0 to 2;

each q is independently an integer from 1 to 4;

X¹ is —C(R¹⁰)—, or —N—;

X² is —O— or —S—;

Y is —O—, —S—, —S(O)—, —S(O)₂—, —N(R¹⁴)—, —C(H)R¹⁵—, or —C(O)—, and m is0, 1, or 2;

R¹⁰ is independently selected from hydrogen, halo, optionallysubstituted alkyl, optionally substituted cycloalkyl, or optionallysubstituted aryl;

R¹⁴ is independently, hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heteroaryl, optionallysubstituted aryl, S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, or—C(O)SR¹²;

R¹⁵ is independently, hydrogen, halo, nitro, cyano, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heteroaryl, optionally substituted aryl, —OR¹², —SR¹²,—N(R¹²)₂, —S(O)_(t)R¹³ (where t is 1 or 2), —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —C(O)SR¹², or —N(R¹²)S(O)_(t)R¹³ (where t is 1 or 2);

and the remainder of, R², R³, R¹², R¹³ and X are as defined above forformula (I); as a single isomer, a mixture of isomers, a racemic mixtureof isomers, a solvate, a hydrate or a prodrug, or as a pharmaceuticallyacceptable salt thereof.

In another embodiment, the compounds provided herein have formula (VI):

wherein K is —O(CH₂)_(q)—, —(CH₂)_(q)O—, or —(CH₂)_(q)O(CH₂)_(q)—;

each q is independently 1 to 4;

Y is —O—, —S—, or —N(R¹⁴)—;

R¹⁰ is optionally substituted lower alkyl;

R¹⁴ is hydrogen, optionally substituted lower alkyl, or —S(O)_(t)R¹³;

R¹³ is lower alkyl; and

t is 1 or 2.

In another embodiment, the compounds provided herein have formula (VI):

wherein K is —(CH₂)_(q)—;

each q is independently 1 to 4;

Y is —O—, —S—, or —N(R¹⁴)—; and

R¹⁴ is hydrogen, optionally substituted lower alkyl, or —S(O)_(t)R¹³(where t is 1 or 2).

In another embodiment, the compounds provided herein have formula (VIa):

or a single isomer, a mixture of isomers, a racemic mixture of isomers,a solvate, a prodrug, or as a pharmaceutically acceptable salt thereof,where the variables are as defined elsewhere herein.

In another aspect, provided herein is a compound of formula (VII):

or a single isomer, a mixture of isomers, a racemic mixture of isomers,a solvate, a prodrug, or as a pharmaceutically acceptable salt thereof,where the variables are as defined elsewhere herein.

In one embodiment, -Z¹Z²Z³-R⁴ is —NHC(O)NH—R⁴ or —C(O)NHR⁴.

In another aspect, provided herein is a compound of formula (VIIa):

or a single isomer, a mixture of isomers, a racemic mixture of isomers,a solvate, a prodrug, or as a pharmaceutically acceptable salt thereof,where the variables are as defined elsewhere herein.

Also of interest are any pharmaceutically acceptable derivatives of thecompounds disclosed herein, including without limitation salts, esters,enol ethers, enol esters, solvates, hydrates, and prodrugs of thecompounds described herein.

Certain exemplary compounds are provided in Tables A, B and C below:

TABLE A

Compound No. R⁴ —Z³—Z²—Z¹— R¹ D2

—NHC(O)N(CH₃)—

E1

—C(O)NH—

E2

—CH₂C(O)NH—

E3

—C(O)NH—

E4

—C(O)NH—

F1

—NHC(O)NH—

F2

—NHC(O)NH—

F3

—NHC(O)NH—

F8

—NHC(O)NH—

TABLE B

Compound No. R^(a) R^(b) B13

H B14 —C(O)OCH₂CH₃ H

TABLE C

Compound R^(a) R^(b) (at 6 position) R^(c) (at 5 position) A1 H H H A2 FH H A3 Me H H A4 —OH H H A5 —OCH3 H H A6

H H A7

H H B1

H H B2 —OCH₂CH₂N(CH₂CH₃)₂ H H B3

H H B4

H H B5

H H B6

H H B7

H H B8

H H B9

H H B10

H H B11 H H

B12 H

H C1 —CH₂C(O)OCH₂CH₃ H H C2 —CH₂C(O)OH H H C3 —CH₂CH₂C(O)OCH₂CH₃ H H C4—CH₂CH₂C(O)OH H H C5

H H C6

H H C7

H H C8 —CH₂CH₂C(O)N(CH₂CH₃)₂ H H C9

H H C10

H H C11

H H C12 —CH₂CH₂C(O)NHCH₂CH₂N(Et)₂ H H C13

H H C14

H H C15

H H C16 —CH₂C(O)NHCH₂CH₂N(Et)₂ H H C17

H H C18

H H C19

H H C20

H H C21

H H C22 —C(O)NHCH₂CH₂N(Et)₂ H H C23

H H C24

H H C25

H H C26 —C(O)OCH₂CH₃ H H C27 —C(O)OH H H D1

H H D3

H H D4

H H D5

H H D6

H H D7

H H D8

H H D9

H H D10

H H

Exemplary compounds provided also include:

-   3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-morpholin-4-yl-ethyl)-propionamide;-   3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-piperidin-1-yl-ethyl)-propionamide;-   3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)-propionamide;-   3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-diethylamino-ethyl)-propionamide;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazin-1-yl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-piperidin-1-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[3-(4-methanesulfonyl-piperazin-1-yl)-propoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea;-   N-(5-tert-Butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-3-oxo-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;-   3-(5-tert-Butyl-isoxazol-3-yl)-1-methyl-1-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;-   N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-morpholin-4-yl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;-   N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(3-piperidin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;-   N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[5-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;-   2-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-morpholin-4-yl-ethyl)-acetamide;-   2-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-piperidin-1-yl-ethyl)-acetamide;-   2-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethyl]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-hydroxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-methoxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-diethylamino-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;-   ethyl    {2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}acetate;-   3-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)    phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}acetic acid;-   pyrrolidine-2-carboxylic acid    2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl    ester;-   ethyl    3-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoate;-   3-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoic    acid;-   3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N,N-diethyl-propionamide;-   2-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-diethylamino-ethyl)-acetamide;-   2-Amino-3-methyl-butyric acid    2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl    ester;-   1-(4-Benzo[d]imidazo[2,1-b]thiazol-2-yl-phenyl)-3-(5-tert-butyl-isoxazol-3-yl)-urea;-   1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-fluoro-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;    and-   1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-methyl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea.

In one embodiment, compounds and compositions provided herein areeffective in methods of modulating the activity of the platelet derivedgrowth factor receptor (PDGFR) subfamily, which includes PDGFR α, PDGFRβ, CSF-1R, c-kit and Flt3.

In one embodiment, compounds and compositions provided herein areeffective to modulate the activity the fetus liver kinase (“flk”)receptor subfamily, which includes kinase insert domain-receptor fetalliver kinase-1 (KDR/FLK-1), flk-1R, flk-4 and fms-like tyrosine kinase 1(fit-1).

In another aspect, compounds and compositions provided herein areeffective to modulate the activity of the “HER” receptor tyrosine kinasesubfamily, which includes EGFR (epithelial growth factor receptor),HER2, HER3 and HER4.

In another aspect, compounds and compositions provided herein areeffective to modulate the activity of the insulin receptor (IR) subfamily which includes insulin-like growth factor I receptor (IGF-1R).

In one embodiment, compounds and compositions provided herein areeffective to modulate the activity of the vascular endothelial growthfactor (“VEGF”) receptor subgroup.

In one embodiment, compounds and compositions provided herein areeffective to modulate the activity of the fibroblast growth factor(“FGF”) receptor subgroup, which includes the receptors FGFR1, FGFR2,FGFR3, and FGFR4, and the ligands, FGF1, FGF2, FGF3, FGF4, FGF5, FGF6,and FGF7.

In another aspect, compounds and compositions provided herein areeffective to modulate the activity of the c-Met receptor family.

In another aspect, compounds and compositions provided herein areeffective to modulate the activity of the Abl protein tyrosine family.

In one embodiment, compounds and compositions provided herein areeffective to modulate the activity of the fms-like tyrosine kinase 3receptor kinase (FLT-3 kinase).

In one embodiment, compounds and compositions provided herein areeffective to modulate the activity of the Src subfamily, which includesSrc, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.

In one embodiment, compounds and compositions provided herein areeffective to modulate the activity of one or more kinases selected fromthe group consisting of sterile 20, sterile 11, sterile, the camk subfamily (calmodulin regulated kinases and related kinases), the AGC subfamily (protein kinase A, protein kinase G and protein kinase C), theCMGC sub family (cdk, map kinase, glycogen synthetase kinase and clk),the sterile 20 sub family, and Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak,Jak and Ack, (and their respective subfamilies).

In another embodiment, provided herein are methods of using thedisclosed compounds and compositions, or pharmaceutically acceptablesalts, solvates, hydrates or prodrugs thereof, for the local or systemictreatment or prophylaxis of human and veterinary diseases, disorders andconditions modulated or otherwise affected mediated via kinase activity.

C. FORMULATION OF PHARMACEUTICAL COMPOSITIONS

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of compounds provided herein that areuseful in the prevention, treatment, or amelioration of protein kinasemediated diseases or one or more of the symptoms thereof.

The compositions contain one or more compounds provided herein. Thecompounds can be formulated into suitable pharmaceutical preparationssuch as solutions, suspensions, tablets, dispersible tablets, pills,capsules, powders, sustained release formulations or elixirs, for oraladministration or in sterile solutions or suspensions for parenteraladministration, as well as transdermal patch preparation and dry powderinhalers. Typically the compounds described above are formulated intopharmaceutical compositions using techniques and procedures well knownin the art.

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable salt, solvate, hydrate or prodrug is(are) mixed with a suitable pharmaceutical carrier or vehicle. Theconcentrations of the compounds in the compositions are effective fordelivery of an amount, upon administration, that treats, prevents, orameliorates one or more of the symptoms of protein kinase mediateddiseases.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as known in the art. Briefly,liposomes such as multilamellar vesicles (MLV's) may be formed by dryingdown egg phosphatidyl choline and brain phosphatidyl serine (7:3 molarratio) on the inside of a flask. A solution of a compound providedherein in phosphate buffered saline lacking divalent cations (PBS) isadded and the flask shaken until the lipid film is dispersed. Theresulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand then extrapolated therefrom for dosages for humans.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to ameliorate one or more of the symptoms ofprotein kinase mediated diseases.

Typically a therapeutically effective dosage should produce a serumconcentration of active ingredient of from about 0.1 ng/ml to about50-100 μg/ml. The pharmaceutical compositions typically should provide adosage of from about 0.001 mg to about 2000 mg of compound per kilogramof body weight per day. Pharmaceutical dosage unit forms are prepared toprovide from about 1 mg to about 1000 mg and in certain embodiments,from about 10 mg to about 500 mg, from about 20 mg to about 250 mg orfrom about 25 mg to about 100 mg of the essential active ingredient or acombination of essential ingredients per dosage unit form. In certainembodiments, the pharmaceutical dosage unit forms are prepared toprovide about 1 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mgor 2000 mg of the essential active ingredient. In certain embodiments,the pharmaceutical dosage unit forms are prepared to provide about 50 mgof the essential active ingredient.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include acids, bases, enolethers and esters, salts, esters, hydrates, solvates and prodrug forms.The derivative is selected such that its pharmacokinetic properties aresuperior to the corresponding neutral compound.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingprotein kinase mediated diseases. The concentration of active compoundin the composition will depend on absorption, inactivation, excretionrates of the active compound, the dosage schedule, amount administered,particular formulation as well as other factors known to those of skillin the art.

The compositions are intended to be administered by a suitable route,including, but not limited to, orally, parenterally, rectally, topicallyand locally. For oral administration, capsules and tablets can beformulated. The compositions are in liquid, semi-liquid or solid formand are formulated in a manner suitable for each route ofadministration.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol, dimethylacetamide or other synthetic solvent; antimicrobial agents, such asbenzyl alcohol and methyl parabens; antioxidants, such as ascorbic acidand sodium bisulfite; chelating agents, such asethylenediaminetetraacetic acid (EDTA); buffers, such as acetates,citrates and phosphates; and agents for the adjustment of tonicity suchas sodium chloride or dextrose. Parenteral preparations can be enclosedin ampules, disposable syringes or single or multiple dose vials made ofglass, plastic or other suitable material.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. In one embodiment, the effective concentration issufficient for ameliorating the symptoms of the disease, disorder orcondition treated and may be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablederivatives thereof. The pharmaceutically therapeutically activecompounds and derivatives thereof are typically formulated andadministered in unit-dosage forms or multiple-dosage forms. Unit-doseforms as used herein refer to physically discrete units suitable forhuman and animal subjects and packaged individually as is known in theart. Each unit-dose contains a predetermined quantity of thetherapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms include ampulesand syringes and individually packaged tablets or capsules. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pints or gallons. Hence, multipledose form is a multiple of unit-doses which are not segregated inpackaging.

Sustained-release preparations can also be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the compound provided herein,which matrices are in the form of shaped articles, e.g., films, ormicrocapsule. Examples of sustained-release matrices include polyesters,hydrogels (for example, poly(2-hydroxyethyl-methacrylate), orpoly(vinylalcohol)), polylactides, copolymers of L-glutamic acid andethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradablelactic acid-glycolic acid copolymers such as the LUPRON DEPOT™(injectable microspheres composed of lactic acid-glycolic acid copolymerand leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. Whilepolymers such as ethylene-vinyl acetate and lactic acid-glycolic acidenable release of molecules for over 100 days, certain hydrogels releaseproteins for shorter time periods. When encapsulated compound remain inthe body for a long time, they may denature or aggregate as a result ofexposure to moisture at 37° C., resulting in a loss of biologicalactivity and possible changes in their structure. Rational strategiescan be devised for stabilization depending on the mechanism of actioninvolved. For example, if the aggregation mechanism is discovered to beintermolecular S—S bond formation through thio-disulfide interchange,stabilization may be achieved by modifying sulfhydryl residues,lyophilizing from acidic solutions, controlling moisture content, usingappropriate additives, and developing specific polymer matrixcompositions

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non-toxic carrier may beprepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain about 0.001%-100% activeingredient, in certain embodiments, about 0.1-85%, typically about75-95%.

The active compounds or pharmaceutically acceptable derivatives may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings.

The compositions may include other active compounds to obtain desiredcombinations of properties. The compounds provided herein, orpharmaceutically acceptable derivatives thereof as described herein, mayalso be advantageously administered for therapeutic or prophylacticpurposes together with another pharmacological agent known in thegeneral art to be of value in treating one or more of the diseases ormedical conditions referred to hereinabove, such as protein kinasemediated diseases. It is to be understood that such combination therapyconstitutes a further aspect of the compositions and methods oftreatment provided herein.

1. Compositions for Oral Administration

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric-coated, sugar-coated or film-coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms, such ascapsules or tablets. The tablets, pills, capsules, troches and the likecan contain any of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic-coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. The activeingredient is a compound or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, because of theenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic adds include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is encapsulated ina gelatin capsule. For a liquid dosage form, the solution, e.g., forexample, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include, but are not limited to, those containing acompound provided herein, a dialkylated mono- or poly-alkylene glycol,including, but not limited to, 1,2-dimethoxymethane, diglyme, triglyme,tetraglyme, polyethylene glycol-350-dimethyl ether, polyethyleneglycol-550-dimethyl ether, polyethylene glycol-750-dimethyl etherwherein 350, 550 and 750 refer to the approximate average molecularweight of the polyethylene glycol, and one or more antioxidants, such asbutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, thiodipropionic acid and its esters, and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl)acetals of lower alkyl aldehydes such as acetaldehydediethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. In one embodiment, the composition is administered asan aqueous solution with hydroxypropyl-beta-cyclodextrin (HPBCD) as anexcipient. In one embodiment, the aqueous solution contains about 1% toabout 50% HPBCD. In one embodiment, the aqueous solution contains about1%, 3%, 5%, 10% or about 20% HPBCD.

Implantation of a slow-release or sustained-release system, such that aconstant level of dosage is maintained is also contemplated herein.Briefly, a compound provided herein is dispersed in a solid innermatrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticizedor unplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,such as more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

3. Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose,hydroxypropyl-beta-cyclodextrin (HPBCD) or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at,typically, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (10-1000 mg,100-500 mg, 10-500 mg, 50-250 mg or 25-100 mg) or multiple dosages ofthe compound. The lyophilized powder can be stored under appropriateconditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, about 5-35 mg, or about 9-30 mg oflyophilized powder, is added per mL of sterile water or other suitablecarrier. The precise amount depends upon the selected compound. Suchamount can be empirically determined.

4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may beformulated as aerosols for topical application, such as by inhalation.These formulations for administration to the respiratory tract can be inthe form of an aerosol or solution for a nebulizer, or as a microfinepowder for insufflation, alone or in combination with an inert carriersuch as lactose. In such a case, the particles of the formulation willtypically have diameters of less than 50 microns or less than 10microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

5. Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The typical weight of a rectalsuppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

6. Sustained Release Compositions

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108,5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830,6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981,6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634,each of which is incorporated herein by reference. Such dosage forms canbe used to provide slow or controlled-release of one or more activeingredients using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active ingredients provided herein.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the agent may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump may be used.In another embodiment, polymeric materials can be used. In yet anotherembodiment, a controlled release system can be placed in proximity ofthe therapeutic target, i.e., thus requiring only a fraction of thesystemic dose. In some embodiments, a controlled release device isintroduced into a subject in proximity of the site of inappropriateimmune activation or a tumor. The active ingredient can be dispersed ina solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient contained in such parenteral compositions is highlydependent on the specific nature thereof, as well as the needs of thesubject.

7. Targeted Formulations

The compounds provided herein, or pharmaceutically acceptablederivatives thereof, may also be formulated to be targeted to aparticular tissue, receptor, or other area of the body of the subject tobe treated. Many such targeting methods are well known to those of skillin the art. All such targeting methods are contemplated herein for usein the instant compositions. For non-limiting examples of targetingmethods, see, e.g., U.S. Pat. Nos. 6,316,652, 6,274,552, 6,271,359,6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082,6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252,5,840,674, 5,759,542 and 5,709,874.

In one embodiment, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable aspharmaceutically acceptable carriers. These may be prepared according tomethods known to those skilled in the art. Briefly, liposomes such asmultilamellar vesicles (MLV's) may be formed by drying down eggphosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) onthe inside of a flask. A solution of a compound provided herein inphosphate buffered saline lacking divalent cations (PBS) is added andthe flask shaken until the lipid film is dispersed. The resultingvesicles are washed to remove unencapsulated compound, pelleted bycentrifugation, and then resuspended in PBS.

D. EVALUATION OF THE ACTIVITY OF THE COMPOUNDS

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possessbiological activities that selectively modulate the activity of kinases.

Such assays include, for example, biochemical assays such as bindingassays, radioactivity incorporation assays, fluorescence polarizationassays, fluorescence resonance energy transfer (FRET) based assays (seegenerally Glickman et al., J. Biomolecular Screening, 7 No. 1 3-10(2002)), as well as a variety of cell based assays.

High throughput screening systems are commercially available (see, e.g.,Zymark Corp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio;Beckman Instruments Inc., Fullerton, Calif.; Precision Systems, Inc.,Natick, Mass.) that enable these assays to be run in a high throughputmode. These systems typically automate entire procedures, including allsample and reagent pipetting, liquid dispensing, timed incubations, andfinal readings of the microplate in detector(s) appropriate for theassay. These configurable systems provide high throughput and rapidstart up as well as a high degree of flexibility and customization. Themanufacturers of such systems provide detailed protocols for varioushigh throughput systems. Thus, for example, Zymark Corp. providestechnical bulletins describing screening systems for detecting themodulation of gene transcription, ligand binding, and the like.

In one embodiment, inhibition is determined in vitro. In a specificembodiment, inhibition is assessed by phosphorylation assays. Anysuitable phosphorylation assay can be employed. For example, membraneautophosphorylation assays, receptor autophosphorylation assays inintact cells, and ELISA's can be employed. See, e.g., Gazit, et al., J.Med. Chem. (1996) 39:2170-2177, Chapter 18 in CURRENT PROTOCOLS INMOLECULAR BIOLOGY (Ausubel, et al., eds. 2001).

In addition a variety of cell based assay methodologies can besuccessfully used in screening assays to identify and profile thespecificity of compounds provided herein. Cells useful in such assaysinclude cells with wildtype or mutated forms. In one embodiment, thewildtype is a kinase that is not constitutively active, but is activatedwith upon dimerization. For example, the mutant FLT3 kinase isconstitutively active via internal tandem duplication mutations or pointmutations in the activation domain. Suitable cells include those derivedthrough cell culture from patient samples as well as cells derived usingroutine molecular biology techniques, e.g., retroviral transduction,transfection, mutagenesis, etc. Exemplary cells include Ba/F3 or 32Dc13cells transduced with, e.g., MSCV retroviral constructs FLT3-ITD (Kellyet al., 2002); Molm-13 and Molm14 cell line (Fujisaki Cell Center,Okayama, Japan); HL60 (AML-M3), AML193 (AML-M5), KG-1, KG-1a, CRL-1873,CRL-9591, and THP-1 (American Tissue Culture Collection, Bethesda, Md.);or any suitable cell line derived from a patient with a hematopoieticmalignancy.

In some embodiments, the compounds described herein significantlyinhibit receptor tyrosine kinases. A significant inhibition of areceptor tyrosine kinase activity refers to an IC₅₀ of less than orequal to 100 μM. In one embodiment, the compound can inhibit activitywith an IC₅₀ of less than or equal to 50 μM, in other embodiment, lessthan or equal to 10 μM, in other embodiment, less than 1 μM, less than100 nM or less than 50 nM. Lower IC₅₀'s are preferred because the IC₅₀provides an indication as to the in vivo effectiveness of the compound.Other factors known in the art, such as compound half-life,biodistribution, and toxicity should also be considered for therapeuticuses. Such factors may enable a compound with a lower IC₅₀ to havegreater in vivo efficacy than a compound having a higher IC₅₀. In oneembodiment, a compound that inhibits activity is administered at a dosewhere the effective tyrosine phosphorylation, i.e., IC₅₀, is less thanits cytotoxic effects, LD₅₀.

Compound binding may also be determined using phage display of fusionproteins exposed on the outer surface of the phage head, for exampleusing an affinity based phage display screening system as described inFabian et al., (Nat Biotechnol. 2005 23(3):329-36). This approachemploys a competition binding assay to determine the relative affinityof a compound of interest to a protein expressed as a fusion protein onthe surface of the T7 bacteriophage. The assay uses phage tagged with akinase of interest and an immobilized bait which are combined with thecompound to be tested. A test compound which binds to the kinasedirectly or indirectly competes with the immobilized bait and preventsthe binding of the phage-tagged kinase to the solid support. If thecompound does not bind to the kinase, the tagged phage can bind to thesolid support through the interaction between the kinase and theimmobilized bait. The results can be read out by quantifying the amountof fusion protein bound to the solid support, which can be accomplishedby either traditional plaque assays or by quantitative PCR (QPCR) usingthe phage genome as a template.

E. METHODS OF USE OF THE COMPOUNDS AND COMPOSITIONS

Also provided herein are methods of using the disclosed compounds andcompositions, or pharmaceutically acceptable salts, solvates, hydratesor prodrugs thereof, for the treatment, prevention, or amelioration of adisease or disorder that is mediated or otherwise affected via proteinkinase activity or one or more symptoms of diseases or disorders thatare mediated or otherwise affected via protein kinase activity (see,Krause and Van Etten, N Engl J Med (2005) 353(2):172-187, Blume-Jensenand Hunter, Nature (2001) 411(17): 355-365 and Plowman et al., DN&P,7:334-339 (1994)). Consistent with the description above, such diseasesor disorders include without limitation:

1) carcinomas include Kit-mediated carcinomas, adenocarcinoma, squamouscell carcinoma, adenosquamous carcinoma, teratocarcinoma, head and neckcancer, brain cancer, intracranial carcinoma, glioblastoma includingPDGFR-mediated glioblastoma, glioblastoma multiforme includingPDGFR-mediated glioblastoma multiforme, neuroblastoma, cancer of thelarynx, multiple endocrine neoplasias 2A and 2B (MENS 2A and MENS 2B)including RET-mediated MENS, thyroid cancer, including sporadic andfamilial medullary thyroid carcinoma, papillary thyroid carcinoma,parathyroid carcinoma including any RET-mediated thyroid carcinoma,follicular thyroid cancer, anaplastic thyroid cancer, bronchialcarcinoid, oat cell carcinoma, lung cancer, small-cell lung cancerincluding flt-3 and/or Kit-mediated small cell lung cancer,stomach/gastric cancer, gastrointestinal cancer, gastrointestinalstromal tumors (GIST) including Kit-mediated GIST and PDGFRα-mediatedGIST, colon cancer, colorectal cancer, pancreatic cancer, islet cellcarcinoma, hepatic/liver cancer, metastases to the liver, bladdercancer, renal cell cancer including PDGFR-mediated renal cell cancer,cancers of the genitourinary tract, ovarian cancer includingKit-mediated and/or PDGFR-mediated ovarian cancer, endometrial cancerincluding CSF-1R-mediated endometrial cancer, cervical cancer, breastcancer including Flt-3-mediated and/or PDGFR-mediated breast cancer,prostate cancer including Kit-mediated prostate cancer, germ cell tumorsincluding Kit-mediated germ cell tumors, seminomas includingKit-mediated seminomas, dysgerminomas, including Kit-mediateddysgerminomas, melanoma including PDGFR-mediated melanoma, metastases tothe bone including CSF-1R-mediated bone metastases, metastatic tumorsincluding VEGFR-mediated tumors, stromal tumors, neuroendocrine tumors,tumor angiogenesis including VEGFR-mediated tumor angiogenesis, mixedmesodermal tumors;

b) sarcomas including PDGFR-mediated sarcomas, osteosarcoma, osteogenicsarcoma, bone cancer, glioma including PDGFR-mediated and/orCSF-1R-mediated glioma, astrocytoma, vascular tumors includingVEGFR-mediated vascular tumors, Kaposi's sarcoma, carcinosarcoma,hemangiosarcomas including VEGFR3-mediated hemangiosarcomas,lymphangiosarcoma including VEGFR3-mediated lymphangiosarcoma;

c) myeloma, leukemia, myeloproliferative diseases, acute myelogenousleukemia (AML) including flt-3 mediated and/or KIT-mediated and/orCSF1R-mediated acute myeloid leukemia, chronic myelogenous leukemias(CML) including Flt-3-mediated and/or PDGFR-mediated chronic myeloidleukemia, myelodysplastic leukemias including Flt-3-mediatedmyelodysplastic leukemia, myelodysplastic syndrome, including Flt-3mediated and/or Kit-mediated myelodysplastic syndrome, idiopathichypereosinophilic syndrome (HES) including PDGFR-mediated HES, chroniceosinophilic leukemia (CEL) including PDGFR-mediated CEL, chronicmyelomonocytic leukemia (CMML), mast cell leukemia includingKit-mediated mast cell leukemia, or systemic mastocytosis includingKit-mediated systemic mastocytosis; and

d) lymphoma, lymphoproliferative diseases, acute lymphoblastic leukemia(ALL), B-cell acute lymphoblastic leukemias, T-cell acute lymphoblasticleukemias, natural killer (NK) cell leukemia, B-cell lymphoma, T-celllymphoma, and natural killer (NK) cell lymphoma, any of which may beFlt-3 mediated and/or PDGFR-mediated, Langerhans cell histiocytosisincluding CSF-1R-mediated and flt-3-mediated Langerhans cellhistiocytosis, mast cell tumors and mastocytosis;

2) Nonmalignant proliferation diseases; atherosclerosis includingPDGFR-mediated atherosclerosis, restenosis following vascularangioplasty including PDGFR-mediated restenosis, and fibroproliferativedisorders such as obliterative bronchiolitis and idiopathicmyelofibrosis, both of which may be PDGFR-mediated;

3) Inflammatory diseases or disorders related to immune dysfunction,immunodeficiency, immunomodulation, autoimmune diseases, tissuetransplant rejection, graft-versus-host disease, wound healing, kidneydisease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis,allergic rhinitis, inflammatory bowel disease including Crohn's diseaseand ulcerative colitis (UC), systemic lupus erythematosis (SLE),arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthmaand chronic obstructive pulmonary disease (COPD), including any of theaforementioned diseases which are flt-3-mediated and/or CSF-1R-mediated;and

4) Infectious diseases mediated either via viral or bacterial pathogensand sepsis, including KIT-mediated sepsis.

Also provided are methods of modulating the activity, or subcellulardistribution, of kinases in a cell, tissue or whole organism, using thecompounds and compositions provided herein, or pharmaceuticallyacceptable derivatives thereof.

Kinases of high interest, i.e. those that mediate one or more of theaforementioned diseases or disorders, include without limitation thefollowing enzymes:

1) The platelet derived growth factor receptor (PDGFR) subfamily, whichincludes PDGFR α, PDGFR β, CSF-1R, Kit and Flt3;

2) The vascular endothelial growth factor (VEGF) receptor subfamily,which includes VEGFR1 (Flt1), VEGFR2 (KDR or Flk1) and VEGFR3 (Flt4);

3) The insulin receptor (IR) subfamily which includes insulin-likegrowth factor I receptor (IGF-1R);

4) Ret;

5) The HER (EGFR) subfamily;

6) The FGFR subfamily;

7) The HGFR (Met) subfamily;

8) The Abl protein tyrosine subfamily;

9) The Src subfamily, which includes Src, Yes1, Fyn, Lyn, Lck, Blk, Hck,Fgr and Yrk;

10) Frk, Btk, Csk, Abl, Syk, Fes, Fps, Fak, Jak and Ack, (and theirrespective subfamilies);

11) A kinase selected form the group consisting of prostate-derivedsterile 20, sterile 11 and sterile 7;

12) the cam kinase subfamily (calmodulin regulated kinases and relatedkinases);

13) the AGC subfamily; and

14) the CMGC sub family (cdk, map kinase, glycogen synthetase kinase andclk).

F. COMBINATION THERAPY

Furthermore, it will be understood by those skilled in the art that thecompounds, isomers, prodrugs and pharmaceutically acceptable derivativesprovided herein, including pharmaceutical compositions and formulationscontaining these compounds, can be used in a wide variety of combinationtherapies to treat the conditions and diseases described above. Thus,also contemplated herein is the use of compounds, isomers, prodrugs andpharmaceutically acceptable derivatives provided herein in combinationwith other active pharmaceutical agents for the treatment of thedisease/conditions described herein.

In one embodiment, such additional pharmaceutical agents include withoutlimitation anti-cancer agents, and anti-inflammatory agents.

The compound or composition provided herein, or pharmaceuticallyacceptable derivative thereof, may be administered simultaneously with,prior to, or after administration of one or more of the above agents.

Pharmaceutical compositions containing a compound provided herein orpharmaceutically acceptable derivative thereof, and one or more of theabove agents are also provided.

Also provided is a combination therapy that treats or prevents the onsetof the symptoms, or associated complications of cancer and relateddiseases and disorders comprising the administration to a subject inneed thereof, of one of the compounds or compositions disclosed herein,or pharmaceutically acceptable derivatives thereof, with one or moreanti-cancer agents.

G. PREPARATION OF THE COMPOUNDS

Starting materials in the synthesis examples provided herein are eitheravailable from commercial sources or via literature procedures (e.g.,March Advanced Organic Chemistry: Reactions, Mechanisms, and Structure,(1992) 4th Ed.; Wiley Interscience, New York). All commerciallyavailable compounds were used without further purification unlessotherwise indicated. CDCl₃ (99.8% D, Cambridge Isotope Laboratories) wasused in all experiments as indicated. Proton (¹H) nuclear magneticresonance (NMR) spectra were recorded on a Bruker Avance 300 MHz NMRspectrometer. Significant peaks are tabulated and typically include:number of protons, and multiplicity (s, singlet; d, double; t, triplet;q, quartet; m, multiplet; br s, broad singlet). Chemical shifts arereported as parts per million (δ) relative to tetramethylsilane. Lowresolution mass spectra (MS) were obtained as electrospray ionization(ESI) mass spectra, which were recorded on a Shimadzu HPLC/MS instrumentusing reverse-phase conditions (acetonitrile/water, 0.05% acetic acid).HPLC was performed using Varian HPLC systems and columns. Flashchromatography was performed using Merck Silica Gel 60 (230-400 mesh)following standard protocol (Still et al. (1978) J. Org. Chem. 43:2923).

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds under standardconditions.

It will also be appreciated by those skilled in the art that in theprocess described below the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R (where R is alkyl, aryl or aralkyl), p-methoxybenzyl,trityl and the like. Suitable protecting groups for carboxylic acidinclude alkyl, aryl or aralkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein. The use of protecting groups is described in detail inGreen, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis(1991), 2nd Ed., Wiley-Interscience.

One of ordinary skill in the art could easily ascertain which choicesfor each substituent are possible for the reaction conditions of eachScheme. Moreover, the substituents are selected from components asindicated in the specification heretofore, and may be attached tostarting materials, intermediates, and/or final products according toschemes known to those of ordinary skill in the art.

Also it will be apparent that the compounds provided herein could existas one or more isomers, that is E/Z isomers, enantiomers and/ordiastereomers.

Compounds of formula (I) may be generally prepared as depicted in thefollowing schemes, unless otherwise noted, the various substituentsR¹—R³, X, Z¹, Z², Z³ and R⁴ are as defined in the Summary section.

GENERAL SYNTHETIC SCHEMES AND EXAMPLES

Various embodiments are further illustrated by the following syntheticschemes and examples, which should not be construed as limiting in anyway. The experimental procedures to generate the data shown arediscussed in more detail below. For all formulations herein, multipledoses may be proportionally compounded as is known in the art. Thecoatings, layers and encapsulations are applied in conventional waysusing equipment customary for these purposes.

The subject matter has been described in an illustrative manner, and itis to be understood that the terminology used is intended to be in thenature of description rather than of limitation. Thus, it will beappreciated by those of skill in the art that conditions such as choiceof solvent, temperature of reaction, volumes, reaction time may varywhile still producing the desired compounds. In addition, one of skillin the art will also appreciate that many of the reagents provided inthe following examples may be substituted with other suitable reagents.See, e.g., Smith & March, Advanced Organic Chemistry, 5^(th) ed. (2001).

Certain ureas may be formed via the creation of isocyanato-intermediatesfollowed by their reaction with aniline derivatives. The initialcreation of the isocyanato intermediate (1) can be achieved via reactionof the corresponding amine derivative in dry toluene at 0° C. via thedropwise addition of trichloromethyl chloroformate (1.1 eq). Typicallythe reaction is stirred at 0° C. and allowed to warm to room temperatureover night. The solvent may then be removed and the resulting mixturerecrystallized in a suitable solvent system, for example ethyl acetate.

Intermediate (1) may then reacted with an appropriately substitutedaniline derivative to form the corresponding urea.

Generally the corresponding isocyanate derivative (1) is reacted with anappropriately substituted aniline (1 eq) dissolved in toluene at anelevated temperature. The reaction is typically allowed to stir at 50°C. for three to six hours. After completion of the reaction, the solventis removed and the mixture purified by HPLC.

Ureas may be converted to thioureas via the use of Lawesson's reagent.In general, Lawesson's reagent is added to the starting urea in tolueneand the reaction heated to 100° C. for 8 hours, then cooled, the solventremoved in vacuo and the thiourea purified by HPLC.

N-substituted ureas may be generated, provided that R does not containreactive primary or secondary amines. Generally a solution of thecorresponding isocyanate in dimethylacetamide is added to a solution ofa corresponding N-alkylbenzenamine derivative, and the mixture is heatedat 80° C. overnight. After cooling to room temperature, water is addedand the mixture is extracted with EtOAc. The combined organic phases arewashed with brine, dried over magnesium sulfate, and evaporated.Purification of the product may be accomplished by Flash chromatography(for example via silica gel, and using hexanes, 0-50% EtOAc as thesolvent system).

Appropriate 2-Amino-6-hydroxybenzo derivatives may be prepared accordingto a slightly modified literature procedure by Lau and Gompf: J. Org.Chem. 1970, 35, 4103-4108. Generally a stirred solution of thiourea orurea in a mixture of ethanol and concentrated hydrochloric acid wasadded a solution of 1,4-benzoquinone in hot ethanol. The reaction istypically stirred for 24 hours at room temperature and then concentratedto dryness. The residue is triturated with hot acetonitrile and theresulting solid filtered and dried. The free base is obtained bydissolving the hydrochloride salt in water, neutralizing with sodiumacetate, and collecting the solid by filtration. The resulting compoundis used below to form the corresponding benzyl derivative.

General Synthesis of Benzothiazole Isomers—Scheme 5

Two benzothiazole isomers shown below (2-amino-benzothiazol-4-ol and2-amino-benzothiazol-6-ol) are commercially available.

The two derivatives that are not commercially available(2-amino-benzothiazol-5-ol and 2-amino-benzothiazol-7-ol) can beobtained by cyclization of 3-methoxyaniline with ammoniumthiocyanatefollowed by demethylation with boron tribromide as outlined in thescheme below:

Ester substitutions on the benzothiazole can be obtained by cyclizationof (4-amino)-phenyl acetic acid with ammoniumthiocyanate followed bymethylation with the dropwise addition of concentrated sulfuric acid inmethanol as outlined below:

The product of the reaction from schemes 4 and 5 is reacted with2′-bromo-4-nitroacetophenone dissolved in ethanol and typically heatedto reflux overnight. The solution is then cooled to 0° C. in anice-water bath and the product collected by vacuum filtration. Afterdrying under vacuum with P₂O₅, the product may be isolated.

Any standard transition metal-mediated reactions as indicated in i, ii,or iii may be used to reduce the nitro group to the amine.Sulfur-mediated reductions or any other reduction methods known to thoseskilled in the art may also be used to reduce the nitro group.Typically, ammonium chloride and iron powder (i) are added to asuspension of the intermediate from Scheme 6 in an appropriate solvent(isopropyl alcohol/water (3:1) or 70% ethanol), then heated to refluxfor 3 hours to overnight with vigorous stirring. The resulting mixtureis filtered through Celite, and the filtercake washed with hot isopropylalcohol (150 mL). The filtrate is concentrated, poured into saturatedsodium bicarbonate, and extracted 3 times with dichloromethane. Thecombined organic phases are dried over MgSO₄ and concentrated to givethe reduced intermediate. In an alternative reaction sequence where R1group is modified into a solubilizing group in the final step, asuspension of the intermediate from Scheme 6 in ethanol can be mixedwith tin chloride (iii) and heated to about 95° C. overnight. Themixture is then diluted with water, pH adjusted to about pH8 withNaHCO₃, and extracted three times with dichloromethane. The combinedorganic phases are dried over MgSO₄ and concentrated to give the reducedintermediate.

A. To form the urea, a suspension of the intermediate above is typicallyreacted with an appropriate isocyanate in toluene or an equivalentaprotic solvent and heated at 40-120° C. overnight. The reaction isquenched by pouring into a mixture of methylene chloride and watercontaining a little MeOH and neutralized with saturated aqueous NaHCO₃solution. The aqueous phase is extracted twice with methylene chloride,the combined organic extracts are dried over MgSO₄ and filtered. Thefiltrate is concentrated and ethyl ether added to precipitate theproduct. The precipitate is collected by filtration, washed with ethylether, and dried under vacuum to give the free base.

B. To form phenyl amides as shown above, generally, an appropriatelysubstituted carboxylic acid is reacted under HOBt(1-hydroxybenzotriazole hydrate) and EDCI(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride)conditions in anhydrous DMF with the appropriately substitutedbenzo[d]imidazo[2,1-b]thiazol-2-yl-phenylamine.

Generally the benzyl derivative is reacted with the appropriatechloroalkyl derivative in dry DMF. To this mixture is added potassiumcarbonate and optionally tetrabutyl ammonium iodide. The suspension isthen heated to 80-90° C. for 5 to 8 hours or until the reaction iscomplete as determined by LCMS. The mixture is cooled to roomtemperature, poured into water, and allowed to sit for 1-3 hours. Theresulting precipitate is collected by vacuum filtration and dried undervacuum. The resulting intermediate after reduction may then be coupledto a urea or amide derivative as depicted in Scheme 7 or 8. In analternative synthetic sequence, this derivatization occurs after thecoupling step to form the urea or amide.

General Scheme for Adding Carbon Chains Substituents—Scheme 10

The length of the carbon chain of the substituent on the benzo-portionof the imidazobenzothiazole ring may be adjusted by using theappropriate 4-amino phenyl carboxylic acid at the step of thebenzothiazole formation (Scheme 5). After the second cyclicization stepwith 2′-bromo-4-nitroacetophenone (Scheme 6), reduction of the nitrogroup (Scheme 7) and coupling to form the amide or urea (Scheme 8), theresulting intermediate may be reacted with an amine to produce the amideanalogs as shown below, which can then be reduced to amine analogs.

Alternatively, at the point of synthesis of[2-(4-nitro-phenyl)-imidazo[2,1b][1,3]benzothiazol-7-yl]acetate as shownbelow, the suspension of acetate may be reacted with lithium hydroxide,then reacted with the amine to form an amide analog, reduced with anynumber of reducing agents such as borane dimethylsulfide to afford analkylamine substitutent and coupled finally with the appropriateisocyanate to produce the urea.

To introduce variations on the R⁴ position, ureas may be prepared in thefollowing manner: An appropriately substitutedbenzo[d]imidazo[2,1-b]thiazol-2-yl]-phenylamine (1 eq.) is dissolved in10 mL aprotic solvent (for example, anhydrous CHCl₃) and cooled to 0° C.Diphosgene or any phosgene equivalent (1.5 eq.) is added and the mixturestirred for 3 h while allowing to warm to room temperature. Afterevaporation of the solvent under vacuum at 20° C., the residue isdissolved in 10 mL anhydrous THF, and 1.4 eq. amine is added and themixture stirred at between 25° C.-125° C. overnight. The solvent isevaporated under vacuum and the crude product purified by HPLC.

3-Amino-5-tert-butyl isoxazole in toluene and CH₂Cl₂ is cooled to −20°C. When the temperature reaches <10° C., triphosgene is added in oneportion. Cooling is continued to <−20° C. Triethylamine in toluene isadded drop-wise over 60 minutes at −20° C. to −15° C. The reactionmixture is stirred for 30 minutes at −20° C. to −15° C. after completionof the addition. The reaction is monitored by TLC: TLC should indicate˜80% isocynate formation.

In certain embodiment, acid salts of the compounds provided herein canbe prepared by addition of acid, including excess acid, to the free baseprepared as described herein.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative, and are not to be takenas limitations upon the scope of the subject matter. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse provided herein, may be made without departing from the spirit andscope thereof. U.S. patents and publications referenced herein areincorporated by reference.

EXAMPLES Example 1 Preparation ofN-(5-tert-butyl-isoxazol-3-yl)-N′-imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea[Compound A1]

A. To prepare the intermediate2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazole, 2-aminobenzothiazole(751 mg, 5 mmol) and 2-bromo-4′-nitroacetophenone (1.22 g, 5 mmol) weredissolved in ethanol and heated to reflux overnight. The solution wasthen cooled at room temperature for 24 hours. The precipitate wascollected by filtration, washed with methanol and dried under vacuum.

B. To prepare the 2-(4-amino-phenyl)imidazo[2,1-b][1,3]benzothiazole,the intermediate from step A (428 mg, 1.5 mmol) was prepared as asuspension in isopropyl alcohol, and to it was added iron powder (419mg, 7.5 mmol). The suspension was heated to reflux overnight withvigorous stirring. Completion of the reaction was confirmed by LCMS. 1NHCl was added to the mixture and allowed to cool to room temperature.The precipitate was collected by filtration and washed with severalvolumes of methanol to dissolve all organic material. The filtrates wereevaporated and azeotroped with toluene. The resulting oil was added tocold saturated NaHCO₃ solution (20 mL) and sonicated. The suspension wasdiluted with toluene and azeotroped. The resulting residue wastriturated with CHCl₃, and the precipitate filtered and washed withCHCl₃. The filtrates were concentrated and purified via Flashchromatography (CH₂Cl₂/5% MeOH/0.5% Et₃N)

C. To prepare the title compound, a suspension of the intermediate fromStep B (133 mg, 0.5 mmol) and 5-tert-butylisoxazole-3-isocyanate (83 mg,0.5 mmol) in methylene chloride was heated to 90° C. for two hours. Theresulting suspension was concentrated and purified via Flashchromatography (CH₂Cl₂/MeOH). ¹H NMR (DMSO-d₆) δ 9.65 (s, 1H), 8.9 (s,1H), 8.7 (s, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.8 (d, 2H), 7.65 (m, 3H),7.4 (t, 1H), 6.55 (s, 1H), 1.3 (s, 9H); LC-MS (ESI) 432 (M+H)⁺

D. The following compounds were prepared from the appropriatelyfunctionalized 2-aminobenzothiazoles by cyclization with2-bromo-4′-nitro acetophenone, followed by reduction and coupling withisoxazole isocyanate under reaction conditions described in Steps B andC.

1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-fluoro-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;LC-MS (ESI) 450 (M+H)⁺; [Compound A2]

1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-methyl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;LC-MS (ESI) 445 (M+H)⁺; [Compound A3]

1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-hydroxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;¹H NMR (CDCl₃) 10.0 (s, 1H); 9.6 (s, 1H); 8.9 (s, 1H); 8.6 (s, 1H); 7.9(m, 3H); 7.6 (m, 2H); 7.4 (s, 1H); 6.7 (s, 1H); 1.4 (s, 9H); and[Compound A4]

1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-methoxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;¹H NMR (methanol-d₄) 8.3 (s, 1H); 7.8 (d, 3H); 7.5 (m, 4H); 7.2 (d, 1H);6.4 (s, 1H); 3.8 (s, 3H); 1.4 (s, 9H). [Compound A5]

Example 2 Preparation of1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-morpholin-4-yl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;[Compound A6]

A. Preparation of the intermediate6-morpholin-4-yl-benzothiazol-2-amine: To a solution of4-N-morpholinoaniline (1.78 g, 10 mmol) in acetic acid (20 mL) was addedNH₄SCN (2.28 g, 30 mmol) in small amounts several times. After stirringthe mixture for 30 minutes, a solution of bromine in acetic acid (1.6 gin 5 mL) was added to the mixture and stirred overnight at roomtemperature. The mixture was then heated at 90° C. for 30 minutes, andthen was cooled and neutralized with saturated NaHCO₃, and thenextracted three times with CH₂Cl₂. The combined organic phases weredried over MgSO₄ and concentrated to dryness. To the residue was added30 mL of 10% HCl and neutralized with saturated NaHCO₃, to give a brownsolid (1.541 g, 66%).

B. Preparation of the intermediate7-morpholin-4-yl-2-(4-nitro-phenyl)-imidazo[2,1-b][1,3]benzothiazole: Amixture of the intermediate from Step A (0.300 g, 1.27 mmol) and2-bromo-4′-nitroacetophenone (0.341 g, 1.4 mmol) was combined in ethanol(10 mL) and heated to reflux overnight. The reaction was quenched withsaturated NaHCO₃ and extracted with ethylacetate. The extract wasconcentrated and purified by SiO₂-Flash chromatography using 0-100%ethylacetate/hexane to give a brown solid (0.211 g, 44%).

C. Preparation of4-(7-morpholin-4-yl-imidazo[2,1-b][1,3]benzothiazol-2-yl)phenylamine: Amixture of the intermediate from Step B (0.200 g, 0.53 mmol) andSnCl₂.2H₂O (0.600 g, 2.65 mmol) in ethanol (10 mL) was heated at 95° C.overnight. Completion of the reaction was confirmed by LCMS. The mixturewas poured into 40 mL water and the pH was adjusted to 8 using saturatedNaHCO₃, and then extracted three times with CH₂Cl₂. The combined organicphases were dried over MgSO₄ and concentrated. The residue was purifiedby SiO₂-Flash chromatography using methanol/ethyl acetate as eluants togive the reduced intermediate (0.112 g, 61%).

D. Preparation of the title compound: To a suspension of theintermediate in Step B (0.110 g, 0.3 mmol), was added5-(tert-butyl)isoxazole-3-isocyanate (0.052 g, 0.3 mmol) in THF (10 mL)and heated to reflux overnight. Completion of the reaction was confirmedby LCMS. After removal of THF, the residue was purified by SiO₂-Flashchromatography using methanol/ethyl acetate as eluants to give the titlecompound as a solid (0.042 g, 27%); ¹H NMR (CDCl₃) δ 9.3 (br, 1H), 7.84(d and s, 3H), 7.60 (d, 2H), 7.50 (d and s, 2H), 7.19 (s, 1H), 7.04 (d,1H), 5.84 (s, 1H), 3.90 (t, 4H), 3.19 (t, 4H), 1.36 (s, 9H).

E.1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazin-1-yl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea.was prepared in a manner similar to Steps A-D, except that in Step A,6-morpholin-4-ylbenzothiazol-2-ylamine was substituted with6-(4-methylpiperazin-1-yl)-1,3-benzothiazol-2-amine. ¹H NMR (CDCl₃) δ9.3 (br, 1H), 7.84 (d and s, 3H), 7.59 (br, 1H), 7.56 (d, 2H), 7.49 (d,1H), 7.20 (d, 1H), 7.05 (dd, 1H), 5.86 (s, 1H), 3.250 (t, 4H), 2.62 (t,4H), 2.38 (s, 3H), 1.36 (s, 9H). [Compound A7]

Example 3 Preparation ofN-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea[Compound B1]

A. The intermediate 2-amino-1,3-benzothiazol-6-ol was prepared accordingto a slightly modified literature procedure by Lau and Gompf: J. Org.Chem. 1970, 35, 4103-4108. To a stirred solution of thiourea (7.6 g,0.10 mol) in a mixture of 200 mL ethanol and 9 mL concentratedhydrochloric acid was added a solution of 1,4-benzoquinone (21.6 g, 0.20mol) in 400 mL of hot ethanol. The reaction was stirred for 24 hours atroom temperature and then concentrated to dryness. The residue wastriturated with hot acetonitrile and the resulting solid was filteredand dried.

The free base was obtained by dissolving the hydrochloride salt inwater, neutralizing with sodium acetate, and collecting the solid byfiltration. The product (2-amino-1,3-benzothiazol-6-ol) was obtained asa dark solid that was pure by LCMS (M+H=167) and NMR. Yield: 13.0 g(78%). NMR (DMSO-d₆) δ7.6 (m, 2H), 6.6 (d, 1H).

B. To prepare the intermediate2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol,2-amino-1,3-benzothiazol-6-ol, (20.0 g, 0.12 mol) and2-bromo-4′-nitroacetophenone (29.3 g, 0.12 mol) were dissolved in 600 mLethanol and heated to reflux overnight. The solution was then cooled to0° C. in an ice-water bath and the product was collected by vacuumfiltration. After drying under vacuum with P₂O₅, the intermediate(2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol) was isolated asa yellow solid. Yield: 17.0 g (46%) NMR (DMSO-d₆) δ 10 (s, 1H), 8.9 (s,1H), 8.3 (d, 2H), 8.1 (d, 2H), 7.8 (d, 1H), 7.4 (s, 1H), 6.9 (d, 1H).

C. To make the7-(2-morpholin-4-yl-ethoxy)-2-(4-nitro-phenyl)imidazo[2,1-b][1,3]benzothiazoleintermediate: 2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol,(3.00 g, 9.6 mmol) was suspended in 100 mL dry DMF. To this mixture wasadded potassium carbonate (4.15 g, 30 mmol, 3 eq), chloroethylmorpholine hydrochloride (4.65 g, 25 mmol, 2.5 eq) and optionallytetrabutyl ammonium iodide (7.39 g, 2 mmol). The suspension was thenheated to 90° C. for 5 hours or until complete by LCMS. The mixture wascooled to room temperature, poured into 800 mL water, and allowed tostand for 1 hour. The resulting precipitate was collected by vacuumfiltration and dried under vacuum. The intermediate,(7-(2-morpholin-4-yl-ethoxy)-2-(4-nitro-phenyl)imidazo[2,1-b][1,3]benzothiazole)was carried on without further purification. Yield: 3.87 g (95%) NMR(DMSO-d₆) δ 8.97 (s, 1H), 8.30 (d, 2H), 8.0 (d, 2H), 7.9 (d, 1H), 7.7(s, 1H), 7.2 (d, 1H), 4.1 (t, 2H), 5.6 (m, 4H), 2.7 (t, 2H).

D. To make the intermediate7-(2-morpholin-4-yl-ethoxy)-2-(4-amino-phenyl)imidazo[2,1-b][1,3]benzothiazole:To a suspension of7-(2-morpholin-4-yl-ethoxy)-2-(4-nitro-phenyl)imidazo[2,1-b][1,3]benzothiazole(3.87 g, 9.1 mmol) in 100 mL isopropyl alcohol/water (3:1) was addedammonium chloride (2.00 g, 36.4 mmol) and iron powder (5.04 g, 90.1mmol). The suspension was heated to reflux overnight with vigorousstirring, completion of the reaction was confirmed by LCMS. The mixturewas filtered through Celite, and the filtercake washed with hotisopropyl alcohol (150 mL). The filtrate was concentrated toapproximately ⅓ of the original volume, poured into saturated sodiumbicarbonate, and extracted 3 times with dichloromethane. The combinedorganic phases were dried over MgSO₄ and concentrated to give theproduct as an orange solid containing a small amount (4-6%) of startingmaterial. (Yield: 2.75 g 54%). 80% ethanol/water may be used in theplace of isopropyl alcohol/water—in which case the reaction is virtuallycomplete after 3.5 hours and only traces of starting material areobserved in the product obtained. NMR (DMSO-d₆) δ 8.4 (s, 1H), 7.8 (d,1H), 7.65 (d, 1H), 7.5 (d, 2H), 7.1 (d, 1H), 6.6 (d, 2H), 4.1 (t, 2H),3.6 (m, 4H), 2.7 (t, 2H).

E. A suspension of7-(2-morpholin-4-yl-ethoxy)-2-(4-amino-phenyl)imidazo[2,1-b][1,3]benzothiazole(4.06 g, 10.3 mmol) and 5-tert-butylisoxazole-3-isocyanate (1.994 g, 12mmol) in toluene was heated at 120° C. overnight. The reaction wasquenched by pouring into a mixture of methylene chloride and watercontaining a little methanol and neutralized with saturated aqueousNaHCO₃ solution. The aqueous phase was extracted twice with methylenechloride, the combined organic extracts were dried over MgSO₄ andfiltered. The filtrate was concentrated to about 20 ml volume and ethylether was added resulting in the formation of a solid. The precipitatewas collected by filtration, washed with ethyl ether, and dried undervacuum to give the free base. Yield: 2.342 g (41%) NMR (DMSO-d₆) δ9.6(br, 1H), 8.9 (br, 1H), 8.61 (s, 1H), 7.86 (d, 1H), 7.76 (d, 2H), 7.69(d, 1H), 7.51 (d, 2H), 7.18 (dd, 1H), 6.52 (s, 1H), 4.16 (t, 2H), 3.59(t, 4H), 3.36 (overlapping, 4H), 2.72 (t, 2H), 1.30 (s, 9H). NMR (CDCl₃)δ9.3 (br, 1H), 7.84 (m, 4H), 7.59 (d, 2H), 7.49 (d, 1H), 7.22 (d, 1H),7.03 (dd, 1H), 5.88 (s, 1H), 4.16 (t, 2H), 3.76 (t, 4H), 2.84 (t, 2H),2.61 (t, 4H), 1.37 (s, 9H).

F. For the preparation of the hydrochloride salt,N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}ureahydrochloride, the free base was dissolved in a mixture of 20 mlmethylene chloride and 1 ml methanol. A solution of 1.0 M HCl in ethylether (1.1 eq.) was added dropwise, followed by addition of ethyl ether.The precipitate was collected by filtration or centrifugation and washedwith ethyl ether to give the hydrochloride salt. Yield: 2.44 g (98%) NMR(DMSO-d₆) δ 11.0 (br, 1H), 9.68 (s, 1H), 9.26 (s, 1H), 8.66 (s, 1H),7.93 (d, 1H), 7.78 (m, 3H), 7.53 (d, 2H), 7.26 (dd, 1H), 6.53 (s, 1H),4.50 (t, 2H), 3.97 (m, 2H), 3.81 (t, 2H), 3.6 (overlapping, 4H), 3.23(m, 2H), 1.30 (s, 9H).

G. Alternatively, Compound B1 may be made by taking the intermediatefrom Example 4B and reacting it with chloroethyl morpholinehydrochloride under conditions described in Step C.

H.N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[5-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}ureahydrochloride, a compound having the general formula (I) where R¹ issubstituted on the 5 position of the tricyclic ring, was prepared in themanner described in Steps A-F but using the cyclization product2-amino-benzothiazol-4-ol with 2-bromo-4′-nitroacetophenone in Step A.¹H NMR (DMSO-d₆) δ 11.6 (br, 1H), 9.78 (br, 1H), 9.56 (br, 1H), 8.64 (s,1H), 7.94 (d, 2H), 7.70 (s, 1H), 7.56 (d, 2H), 7.45 (t, 1H), 7.33 (d,1H), 6.54 (s, 1H), 4.79 (t, 2H), 3.87 (m, 6H), 3.60 (m, 2H), 3.34 (m,2H), 1.30 (s, 9H); LC-MS: ESI 561 (M+H)+. [Compound B11]

I.N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[6-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}ureahydrochloride [Compound B12] was also prepared by first preparing thebenzothiazole starting material, 5 methoxy-benzothiazol-2-yl-amine:

To prepare the 5-methoxy-benzothiazol-2-ylamine starting material: To asuspension of (3-methoxy-phenyl)-thiourea (1.822 g, 10 mmol) in CH₂Cl₂(20 mL) at 0° C. was added dropwise a solution of bromine (1.76 g, 11mmol) in 10 ml of trichloromethane over a period of thirty minutes. Thereaction was stirred for 3 hours at room temperature then heated to 3hours to reflux for one hour. The precipitate was filtered and washedwith dichloromethane. The solid was suspended in saturated NaHCO₃ andextracted with CH₂Cl₂. The extract was dried over MgSO₄ and concentratedto give a white solid (1.716 g, 95%).

To prepare the 2-amino-benzothiazol-5-ol: To a suspension of5-methoxy-benzothiazol-2-ylamine in 16 mL of 48% HBr/H2O was heated to105° C. in an oil bath for 10 hours. After the reaction was cooled toroom temperature, the precipitate was collected by filtration and washedwith acetone. The filtrate was suspended in saturated NaHCO₃ andextracted with CH₂Cl₂. The extract was dried over MgSO₄ and concentratedto give a white solid (0.986 g, 63%).

N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[6-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}ureahydrochloride 2-amino-benzothiazol-5-ol from the previous step andfollowing the method described in ¹H NMR (DMSO-d₆) δ 11.1 (br, 1H), 9.69(br, 1H), 9.28 (br, 1H), 8.71 (s, 1H), 7.97 (d, 1H), 7.79 (d and s, 3H),7.56 (d, 2H), 7.13 (dd, 1H), 6.53 (s, 1H), 4.56 (t, 2H), 3.98 (m, 2H),3.82 (t, 2H), 3.65 (m, 2H), 3.55 (m, 2H), 3.25 (m, 2H), 1.31 (s, 9H);LC-MS: ESI 561 (M+H)⁺. [Compound B12]

J.N-(5-tert-butyl-isoxazol-3-yl)-N′-{3-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}ureawas prepared in a manner described in Steps A-E, but in which2-bromo-3′-nitroacetophenone replaced 2-bromo-4′-nitroacetophenone inStep B; ¹H NMR (DMSO-d₆) δ 11.1 (br, 1H), 9.76 (s, 1H), 9.34 (s, 1H),8.76 (s, 1H), 8.01 (s, 1H), 8.05 (d, 1H), 7.79 (d, 1H), 7.50 (d, 1H),7.37 (t, 1H), 7.32 (s, 1H), 7.27 (dd, 1H), 6.55 (s, 1H), 4.51 (t, 2H),3.98 (m, 2H), 3.83 (t, 2H), 3.61 (m, 4H), 3.24 (m, 2H), 1.31 (s, 9H);LC-MS ESI: MH⁺ 561. [Compound B13]

K.2-{3-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-imidazo[2,1-b][1,3]benzothiazole-7-carboxylicacid ethyl ester was prepared in a manner described in Steps A-E, but inwhich Step B is carried out in the following manner: A mixture of2-amino-benzothiazole-6-carboxylic acid ethyl ester (0.889 g, 4 mmol)and 2-bromo-3′-nitroacetophenone (1.220 g, 5 mmol) in DME (15 mL) wasstirred at room temperature overnight. After the removal of DME,2-methoxyethanol was added and heated at 140° C. for 4 hours. A yellowsolid was formed, which was filtered, washed with ethanol anddiethylether, and dried under vacuum (0.964 g, 66%); ¹H NMR (DMSO-d₆) δ9.60 (s, 1H), 8.96 (s, 1H), 8.64 (s, 1H), 8.70 (d, 1H), 8.14 (s, 3H),7.52 (dd, 1H), 7.36 (t, 1H), 7.39 (t, 1H), 6.54 (s, 1H), 4.36 (q, 2H),1.36 (t, 3H), 1.31 (s, 9H); LC-MS ESI: MH⁺ 504. [Compound B14]

Example 4 Preparation of1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-diethylamino-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea[Compound B2]

A. To a suspension of the intermediate2-(4-Nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol from Example 3B(2.24 g, 7.2 mmol) in ethanol (40 mL) was added SnCl₂.H₂0 (7.90 g, 35mmol) and heated to reflux. Concentrated HCl was added to the reactionmixture and the precipitate formed gradually. The reaction mixture washeated to reflux for 20 hours and then allowed to cool to roomtemperature. The solution was poured into ice and neutralized with 10%NaOH and adjusted to approximately pH 6. The organic phase was extractedthree times with ethylacetate (80 mL×3). Extracts were dried over MgSO₄and concentrated to give a yellow solid. (1.621 g, 80%).

B. To a suspension of the intermediate from Step A (1.00 g, 3.55 mmol)in THF (20 mL) was added 5-tert-butylisoxazole-3-isocyanate (0.650 g,3.9 mmol) and heated to reflux overnight in an oil bath at 90° C.Completion of reaction was verified by LC-MS. The solvent was removedand the resulting mixture was dissolved in methanol which was removed togive the second intermediate as a solid (1.103 g, 69%).

C. To a solution of1-(5-tert-butyl-isoxazol-3-yl)-3-[4-(7-hydroxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea(0.25 g, 0.56 mmol) from Step B, 2-diethylamino-ethanol (0.094 g, 0.8mmol), and triphenylphosphine (0.168 g, 0.8 mmol) in THF (6 mL) wasdropped a solution of diisopropyl azodicarboxylate (0.162 g, 0.8 mmol)in THF (3 mL). The mixture was stirred at room temperature overnight.After solvent was evaporated, the residue was purified by preparativeHPLC (C18 column eluting with MeCN/H₂O containing 0.05% AcOH). Theappropriate fractions were combined, neutralized with saturated NaHCO₃solution, and extracted with CH₂Cl₂. Extracts were dried over MgSO₄ andconcentrated to give the product as solid. ¹H NMR (CDCl₃) δ 9.3 (br,1H), 8.3 (br, 1H), 7.83 (s, 1H), 8.81 (d, 2H), 7.56 (d, 2H), 7.47 (d,1H), 7.20 (d, 1H), 7.0 (dd, 1H), 5.94 (s, 1H), 4.09 (t, 2H), 2.91 (t,2H), 2.67 (q, 4H), 1.37 (s, 9H), 1.07 (t, 6H).

D. The free base from Step C (0.020 g) was dissolved in CH₂Cl₂ (0.5 mL)and to the solution was added dropwise 1.0 M HCl/dioxane. A solid wasformed and the solvent was removed to afford the hydrochloride salt(0.020 g). ¹H NMR (DMSO-d₆) δ 10.1 (br, 1H), 9.67 (br, 1H), 9.24 (br,1H), 8.66 (s, 1H), 7.93 (d, 1H), 7.76 (d and s, 3H), 7.54 (d, 2H), 7.24(dd, 1H), 6.53 (s, 1H), 4.44 (t, 2H), 3.24 (m, 6H), 1.29 (s, 9H), 1.24(t, 6H).

E. Alternative reaction sequence for Compound B2: To a suspension of theintermediate 2-(4-Nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-ol fromExample 3B (1.00 g, 3.2 mmol) in DMF (15 mL) was added potassiumcarbonate (1.38 g, 10 mmol) and (2-chloro-ethyl)diethylaminehydrochloride (0.826 g, 4.8 mmol) was heated to 80° C. overnight.Completion of the reaction was confirmed by LC-MS. 80 mL of water wasadded to the mixture, filtered and washed with water and diethylether togive the first intermediate as a yellow solid. The yellow solidintermediate was moved to a flask, and ammonium chloride (0.513 g, 9.6mmol) and 80% ethanol (30 mL) was added and the mixture was heated toreflux at 100° C., at which point iron powder (1.787 g, 32 mmol) wasadded and the mixture continued to reflux at 100° C. for 3 hours.Completion of the reaction was confirmed by LC-MS. Ethanol (30 mL) wasadded to the mixture and heated. The precipitate was filtered and washedwith hot ethanol. Saturated NaHCO₃ was added to the solution and theorganic layer was extracted with CH₂Cl₂ and dried over MgSO₄ andconcentrated to give the second intermediate as a solid (1.089 g). Asuspension of this second intermediate (1.08 g, 2.8 mmol) in toluene (20mL) was added 5-tert-butylisoxazole-3-isocyanate (0.605 g, 3.64 mmol)and the reaction was heated to 120° C. overnight. The reaction wasquenched with CH₂Cl₂ and water with methanol, and basified withsaturated NaHCO₃ to pH of about 8. The aqueous layer was extracted twicewith CH₂Cl₂. The organic layers were combined, dried over MgSO₄ andconcentrated to give the final product [Compound B2]. To the residue waspurified by preparative HPLC (C18 column eluting with 35-65% CH₃CN/H₂Ocontaining 0.05% AcOH). The appropriate fractions were combined, theacetonitrile removed, and extracted with CH₂Cl₂. The extracts were driedover MgSO₄ and concentrated to give a white solid (0.894 g).

F. The compounds below were prepared in the manner described in StepsA-D:

1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-piperidin-1-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureahydrochloride; ¹H NMR (CDCl₃) δ 9.3 (br, 1H), 8.9 (br, 1H), 8.84 (s,1H), 8.82 (d, 2H), 7.57 (d, 2H), 7.47 (d, 1H), 7.20 (d, 1H), 7.0 (dd,1H), 5.89 (s, 1H), 4.15 (t, 2H), 2.81 (t, 2H), 2.53 (t, 4H), 1.63 (m,4H), 1.5 (m, 2H), 1.37 (s, 9H). [Compound B3]

and1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-ureahydrochloride; ¹H NMR (CDCl₃) δ 9.3 (br, 1H), 7.85 (s, 1H), 7.81 (d,2H), 7.75 (br, 1H), 7.59 (d, 2H), 7.48 (d, 1H), 7.22 (d, 1H), 7.0 (dd,1H), 5.87 (s, 1H), 4.16 (t, 2H), 2.87 (t, 2H), 2.65 (br, 4H), 2.5 (br,4H), 2.31 (s, 3H), 1.37 (s, 9H). [Compound B4]

Example 5 Preparation of (2r)-2-amino-3-methyl-butyric acid2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-ylester [Compound B5]

A. The title compound was prepared in a manner similar to Example 3, butwhere the phenolic urea (0.125 g, 0.3 mmoles) was dissolved in anhydrousDMF (3 mL). To this solution was added potassium carbonate (0.082 g, 0.6mmoles) and the Boc-L-valine N-hydroxysuccinimide (0.6 mmoles). Thesolution was stirred overnight at room temperature and then concentratedto dryness. The resulting solid was purified using HPLC with theappropriate fractions collected. These were concentrated to dryness andthe resulting solid dissolved in methanol, and the solution treated with4 M HCl in dioxane (2 mL). When cleavage of the Boc protecting group wascomplete by mass spectroscopy, the solution was concentrated to dryness.The solid was again dissolved in a minimal volume of methanol, and thehydrochloride precipitated by the addition of ethyl ether. NMR (DMSO-d₆)8.2 (s, 1H); 7.8 (s, 1H); 7.7 (d, 1H); 7.6 (d, 2H); 7.5 (s, 2H); 7.4 (s,1H); 7.2 (d, 2H); 6.6 (s, 1H); 6.3 (s, 1H); 4.2 (s, 1H); 2.2 (m, 1H);1.3 (s, 9H); 1.0 (m, 6H). LC-MS: ESI 582 (M+H)⁺.

B. In a manner similar to Step A, (2S)-pyrrolidine-2-carboxylic acid2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-ylester was made using Boc-L-proline N-hydroxysuccinimide; LC-MS: ESI 545(M+H)⁺. [Compound B6]

Example 6 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureahydrochloride; [Compound B7]

A. The title compound was prepared in the manner described in Example4A-D, but in which 2-diethylamino-ethanol was replaced with3-morpholin-4-yl-propan-1-ol at Step C. ¹H NMR (CDCl₃) δ 9.35 (br, 1H),7.87 (s, 1H), 7.83 (d, 2H), 7.59 (d, 2H), 7.51 (d, 1H), 7.45 (s, 1H),7.22 (d, 1H), 7.02 (dd, 1H), 5.84 (s, 1H), 4.08 (t, 2H), 3.74 (t, 4H),2.53 (m, 6H), 2.01 (m, 2H), 1.37 (s, 9H), LC-MS: ESI 575 (M+H)⁺.

Example 7 Preparation of1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{7-[3-(4-methanesulfonyl-piperazin-1-yl)-propoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea.[Compound B10]

A. To prepare the intermediate7-(3-chloro-propoxy)-2-(4-nitro-phenyl)-imidazo[2,1-b][1,3}benzothiazole,the intermediate from Example 3B (0.500 g, 1.6 mmol) was suspended inDMF, and to the suspension was added potassium carbonate (0.221 g, 1.6mmol) and 1-bromo-4-chloropropane (0.756 g, 4.8 mmol). The suspensionwas then heated to 80° C. overnight. The mixture was concentrated todryness and the crude product purified by Flash chromatography withsilica gel using 1:1 ethanol/hexane (0.440 g, 85%).

B. To prepare the intermediate7-[3-(4-methanesulfonyl-piperazin-1-yl)-propoxy]-2-(4-nitro-phenyl)-imidazo[2,1-b][1,3]benzothiazole,the intermediate from Step A (1.37 g, 3.5 mmol) was suspended in DMF,and to the suspension was added tetrabutylammonium iodide (0.150 g) and1-methane sulfonyl piperazine (1.20 g, 7.0 mmol). The suspension wasthen heated to 90° C. overnight. After the reaction was completed themixture was poured into water, and filtered.

C. For reduction of the nitro intermediate from Step B to the amine: tothe suspension of the intermediate from Step B in isopropyl alcohol (45mL) was added 10% HCl, (5 mL) and iron powder (1.82 g). The suspensionwas heated to reflux for 2 hours and the completion of the reaction wasverified by LCMS. The mixture was filtered and washed with methanol andDCM. The filtrate was concentrated, poured into saturated sodiumbicarbonate and extracted three times with dichloromethane, (Yield: 1.00g, 2.6 mmol).

D. Preparation of the title compound: to the intermediate from the StepC was dissolved in chloroform, was added5-tert-butylisoxazole-3-isocyanate (0.431 g, 2.6 mmol) and the mixturewas heated to reflux for approximately 3 hours. The crude product waspurified by Flash chromatography with silica gel using a 5-20%methanol/DCM with 0.5% triethylamine. ¹H NMR (DMSO-d₆) 9.8 (s, 1H); 9.5(s, 1H); 8.8 (s, 1H); 8.0 (d, 1H); 7.7 (m, 3H); 7.6 (d, 2H); 7.2 (d,1H); 6.5 (s, 1H); 4.3 (m, 3H); 3.7 (m, 5H); 3.4 (m, 4H); 3.2 (m, 1H);3.0 (s, 3H); 2.3 (m, 2H); 1.3 (s, 9H).

E. The following compounds were made in the manner described in StepsA-D but using the appropriate secondary amine in Step B.

1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-thiomorpholin-4-yl-propoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;¹H NMR (DMSO-d₆) 11 (s, 1H); 9.7 (s, 1H); 9.3 (s, 1H); 8.7 (s, 1H); 7.9(d, 2H); 7.8 (m, 3H); 7.5 (m, 2H); 7.2 (d, 1H); 6.5 (s, 1H); [CompoundB8] and1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea;¹H NMR (methanol-d₄) 8 (s, 1H); 7.7 (d, 2H); 7.6 (d, 1H); 7.5 (d, 2H);6.9 (m, 1H); 6.4 (s, 1H); 3.9 (m, 1H); 3.3 (s, 3H); 2.5 (m, 8H); 2.3 (s,3H); 1.8 (m, 2H); 1.3 (s, 9H); [Compound B9]

Example 8 Preparation of Ethyl2-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}acetate[CompoundC1]

A. To prepare the intermediate (2-amino-1,3-benzothiazol-6-yl)aceticacid, a solution of bromine (2.3 mL) in 10 mL acetic acid was addeddropwise over 30 min to a solution of (4-aminophenyl)acetic acid (7.00g, 46.3 mmol) and NH₄SCN (7.00 g, 92 mmol) in 90% acetic acid (100 mL)at 0° C. After addition was completed, the cold bath was removed and thereaction mixture was stirred at room temperature for 4 hours. Water (300mL) was added to the mixture followed by sodium carbonate until pH 5.The resulting yellow precipitate was collected by filtration, washedwith water and ether, and dried under vacuum with P₂O₅ to give theproduct as yellow solid. Yield: 7.89 g (82

¹H NMR (DMSO-d₆) δ 7.51 (s, 1H), 7.40 (br, 2H), 7.24 (d, 1H), 7.07 (d,1H), 3.50 (s, 2H); LC-MS: ESI 209 (M+H)⁺.

B. To prepare the intermediate methyl(2-amino-benzothiazol-6-yl)acetate, 2 mL concentrated H₂SO₄ was addeddropwise to a solution of (2-amino-1,3-benzothiazol-6-yl)acetic acid(7.89 g, 37.9 mmol) in 200 mL methanol and the reaction mixture washeated at 50° C. for 90 minutes. After evaporation of most of themethanol, dichloromethane (150 mL) was added and the mixture wasneutralized with saturated NaHCO₃ solution. The aqueous phase wasextracted with dichloromethane. The organic extracts were combined,dried over MgSO₄, and concentrated to give the product as a yellow solid(6.51 g, 77%). ¹H NMR (DMSO-d₆) δ 7.54 (s, 1H), 7.44 (br, 2H), 7.27 (d,1H), 7.09 (d, 1H), 3.66 (s, 2H), 3.61 (s, 3H); LC-MS: ESI 223 (M+H)⁺.

C. To prepare the intermediate methyl[2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]acetate, amixture of methyl (2-amino-1,3-benzothiazol-6-yl)acetate (6.26 g, 28mmol) and 2-bromo-4′-nitroacetophenone (8.786 g, 36 mmol) in absoluteethanol (80 mL) was heated at 90° C. for 12 hours. A yellow solid wasformed, collected by filtration, washed with ethanol, and dried undervacuum to give the product as yellow solid (5.01 g, 48%). ¹H NMR(DMSO-d₆) δ 9.07 (s, 1H), 8.32 (d, 2H), 8.12 (d, 2H), 7.97 (s, 1H and d,2H), 7.50 (d, 1H), 3.84 (s, 2H), 3.65 (s, 3H); LC-MS: ESI 368 (M+H)⁺.

D. To make ethyl[2-(4-aminophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]acetateintermediate: a mixture of methyl[2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]acetate (5.00 g,13.6 mmol) and tin(II) chloride dihydrate (15.795 g, 70 mmol) in ethanol(150 mL) was heated at 95° C. for 8 hours. Additional tin(II) chloridedihydrate was added and stirred at 95° C. over night. The reaction wasquenched with water (200 mL) and dichloromethane (500 mL), and the pHwas adjusted to about 7 with 10% sodium hydroxide. The aqueous phase wasextracted with dichloromethane, the combined organic extracts were driedover MgSO₄ and concentrated. The residue was taken up in dichloromethaneand ether and allowed to stand overnight to form a yellow solid whichwas filtered off and dried to give the product as yellow solid (2.55 g,53%). ¹H NMR (DMSO-d₆) δ 8.4 (s, 1H), 7.87 (m, 2H), 7.49 (d, 2H), 7.40(d, 1H), 6.60 (d, 2H), 5.19 (s, 2H), 4.07 (q, 2H), 3.79 (s, 2H), 1.18(t, 3H); LC-MS: ESI 352 (M+H)⁺.

E. To prepare the title compound, a mixture of ethyl[2-(4-aminophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]acetate (2.50 g,7.1 mmol) and 5-tert-butyl-3-isocyanatoisoxazole (1.412 g, 8.5 mmol) intoluene (60 mL) was heated at 110° C. over night. The precipitate wascollected by filtration, washed with ether, and dried under vacuum togive the product as white solid (3.592 g, 98%). ¹H NMR (DMSO-d₆) δ 9.54(s, 1H), 8.89 (s, 1H), 8.67 (s, 1H), 7.93 (s, 1H), 7.90 (d, 1H), 7.80(d, 2H), 7.53 (d, 2H), 7.47 (d, 1H), 6.53 (s, 1H), 4.11 (q, 2H), 3.81(s, 2H), 1.31 (s, 9H), 1.20 (t, 3H); LC-MS: ESI 518 (M+H)⁺.

Example 9 Preparation of2-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}aceticacid [Compound C2]

A. To a suspension of ethyl2-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}acetatefrom Example 8, (2.00 g, 3.86 mmol) in 30 mL THF was added lithiumhydroxide monohydrate (0.966 g, 23 mmol) and 15 mL water. The reactionmixture was stirred at room temperature over night. After evaporation ofTHF, the aqueous mixture was acidified with 10% HCl solution to pH 6. Awhite solid was formed, collected by filtration, washed with water andether, and dried under vacuum with P₂O₅ to give the product as whitesolid (1.815 g, 96%). ¹H NMR (DMSO-d₆) δ 12.4 (br, 1H), 9.58 (s, 1H),8.94 (s, 1H), 8.68 (s, 1H), 7.92 (s, 1H), 7.90 (d, 1H), 7.80 (d, 2H),7.54 (d, 2H), 7.45 (d, 1H), 6.53 (s, 1H), 3.72 (s, 2H), 1.30 (s, 9H);LC-MS: ESI 490 (M+H)⁺.

B. To prepare its sodium salt: to a solution of2-{2-[4-({[(5-tert-butylisoxazole-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazole-7-yl}aceticacid (0.13 g, 0.27 mmol) in MeOH (20 mL) and water (1 mL) was addedsodium methoxide (0.017 g, 0.031 mmol). After MeOH was evaporated, tothe residue was added EtOH, and then was evaporated for three times togive the product as a white solid (0.112 g). ¹H NMR (DMSO-d₆) δ 11.1(br, 1H), 10.25 (br, 1H), 8.45 (s, 1H), 7.74 (m, 2H), 7.44 (d, 3H), 7.1(d, 2H), 6.44 (s, 1H), 3.34 (s, 2H), 1.23 (s, 9H).

Example 10 Preparation of Ethyl3-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoate[Compound C3]

A. To prepare the intermediate3-(2-amino-1,3-benzothiazol-6-yl)propanoic acid, a solution of bromine(3 mL) in 10 mL acetic acid was added dropwise over 30 min to a solutionof 3-(4-aminophenyl)propanoic acid (10.00 g, 60.5 mmol) and NH₄SCN (9.21g, 121 mmol) in 120 mL acetic acid at 0° C. After the addition wascompleted the cold bath was removed and the reaction mixture was stirredat room temperature for 4 hours. Water (300 mL) was added to the mixturefollowed by sodium carbonate until pH 5. The resulting yellowprecipitate was collected by filtration, washed with water and ether,and dried under vacuum with P₂O₅. Yield: 13.425 g (99%) ¹H NMR (DMSO-d₆)δ 12.11 (br, 1H), 7.49 (s, 1H), 7.37 (br, 2H), 7.23 (d, 1H), 7.06 (d,1H), 2.82 (t, 2H), 2.5 (t, 2H, overlap with solvent); LC-MS: ESI 223(M+H)⁺.

B. In preparing the intermediate methyl3-(2-amino-1,3-benzothiazol-6-yl)propanoate), 2 mL concentrated H₂SO₄was added dropwise to a solution of3-(2-amino-1,3-benzothiazol-6-yl)propanoic acid from Step A (13.42 g,60.4 mmol) in methanol (150 mL) and the reaction mixture was stirred atroom temperature over night. After evaporation of most of the solvent,dichloromethane (200 mL) was added and the mixture was neutralized withsaturated NaHCO₃ solution. The aqueous phase was extracted withdichloromethane, the combined organic extracts dried over MgSO₄ andconcentrated to give the product as yellow solid (9.762 g, 68%). ¹H NMR(CDCl₃) δ 7.37 (s, 1H and d, 1H), 7.15 (d, 1H), 5.30 (br, 2H), 3.68 (s,3H), 3.00 (t, 2H), 2.17 (t, 2H); LC-MS: ESI 237 (M+H)⁺.

C. To prepare the intermediate methyl3-[2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]propanoate: Amixture of methyl 3-(2-amino-1,3-benzothiazol-6-yl)propanoate (9.76 g,41.3 mmol) from Step A and 2-bromo-4′-nitroacetophenone (13.178 g, 54mmol) in absolute ethanol (150 mL) was heated at 90° C. for 12 hours. Ayellow solid was formed, collected by filtration, washed with ethanol,and dried under vacuum to give the product as yellow solid (6.015 g,38%). ¹H NMR (DMSO-d₆) δ 9.05 (s, 1H), 8.30 (d, 2H), 8.11 (d, 2H), 7.92(s, 1H), 7.90 (d, 1H), 7.45 (d, 1H), 3.60 (s, 3H), 3.09 (t, 2H), 2.68(t, 2H); LC-MS: ESI 382 (M+H)⁺.

D. To prepare the intermediate ethyl3-[2-(4-aminophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]propanoate: Amixture of methyl3-[2-(4-nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]propanoate(6.01 g, 15.8 mmol) from Step B and tin(II) chloride dehydrate (18.05 g,80 mmol) in ethanol (200 mL) was heated at 90° C. for 12 hours. Thereaction was quenched with 400 mL water and 400 mL dichloromethane andthe pH was adjusted to about 7 with sodium carbonate. The aqueous phasewas extracted with dichloromethane, the combined organic extracts weredried over MgSO₄ and concentrated. The crude product was purified byFlash chromatography with silica gel using a 0-100% hexane/ethyl acetategradient to give the product as a yellow solid (3.824 g, 66%). ¹H NMR(CDCl₃) δ 7.86 (s, 1H), 7.61 (d, 2H), 7.53 (s, 1H), 7.48 (d, 1H), 7.29(d, 1H), 6.75 (d, 2H), 4.14 (q, 2H), 3.73 (br, 2H), 3.06 (t, 2H), 2.67(t, 2H), 1.23 (t, 3H); LC-MS: ESI 366 (M+H)⁺.

E. A mixture of ethyl3-[2-(4-aminophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]propanoate(3.80 g, 10.4 mmol) from Step C and 5-tert-butyl-3-isocyanatoisoxazole(2.08 g, 12.5 mmol) in toluene (80 mL) was heated at 110° C. over night.A precipitate was formed, collected by filtration, washed with ether,and dried under high vacuum to give the title compound as a white solid(5.056 g, 91%). ¹H NMR (DMSO-d₆) δ 9.62 (s, 1H), 9.08 (s, 1H), 8.70 (s,1H), 7.91 (s, 1H), 7.89 (d, 1H), 7.79 (d, 2H), 7.54 (d, 2H), 7.46 (d,1H), 6.53 (s, 1H), 4.06 (q, 2H), 2.98 (t, 2H), 2.70 (t, 2H), 1.30 (s,9H), 1.15 (t, 3H); LC-MS: ESI 532 (M+H)⁺.

F. Preparation of3-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoicacid: To a suspension of ethyl3-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoatefrom Step E (3.00 g, 5.6 mmol) in THF (30 mL) was added lithiumhydroxide monohydrate (1.428 g, 34 mmol) and 20 mL water. The reactionmixture was stirred at room temperature overnight. After evaporation ofthe organic solvent, the aqueous phase was acidified with 10% HClsolution to pH 6. A white solid was formed, collected by filtration,washed with water and ether, and dried under vacuum with P₂O₅ to givethe product as a white solid (2.791 g, 99%). ¹H NMR (DMSO-d₆) δ 9.66 (s,1H), 9.21 (s, 1H), 8.68 (s, 1H), 7.90 (s, 1H), 7.88 (d, 1H), 7.79 (d,2H), 7.54 (d, 2H), 7.46 (d, 1H), 6.53 (s, 1H), 2.95 (t, 2H), 2.62 (t,2H), 1.31 (s, 9H); LC-MS: ESI 503 (M+H)⁺. [Compound C4]

G. The corresponding sodium salt of the product in Step F was preparedin the manner described in Example 9B; ¹H NMR (DMSO-d₆) δ 12.2 (br, 1H),11.2 (br, 1H), 8.58 (s, 1H), 7.9 (d, 1H), 7.81 (s, 1H), 7.5 (d, 1H),7.46 (d, 2H), 7.21 (d, 2H), 6.49 (s, 1H), 2.9 (t, 2H), 2.45 (t, 2H),1.29 (s, 9H).

Example 11 Preparation of2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-imidazo[2,1-b][1,3]benzothiazole-7-carboxylicacid ethyl ester [Compound C26]

A, To prepare the intermediate2-(4-nitro-phenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxylic acidethyl ester, 2-amino-benzothiazole-6-carboxylic acid ethyl ester and2-bromo-4′-nitroacetophenone were combined in 2-methoxy ethanol andstirred at 40° C. for 24 hours. Formation of the intermediate wasconfirmed by LCMS. The reaction was heated further at 140° C. for 18hours, filtered, washed with ethanol and dried under high vacuum toproduce a yellow solid.

B. To prepare the intermediate2-(4-aminophenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxylic acid ethylester, SnCl₂H₂0 (6.770 g, 30 mmol) was added to the intermediate fromStep A (2.204 g, 6 mmol) in ethanol (40 mL), and heated to reflux for 20hours. The reaction was quenched with water, neutralized with saturatedNaHCO₃ and extracted with CH₂Cl₃ with some methanol. The extract wasdried over MgSO₄ and concentrated to give a yellow solid (1.518 g, 75%).

C. To prepare the title compound, a mixture of the intermediate fromStep B (1.51 g, 4.48 mmol) and 5-tert-butyl-3-isocyanatoisoxazole (997mg, 6 mmol) in toluene (40 mL) was heated at 100° C. overnight. Theformation of the product was confirmed by LC-MS. The precipitate wascollected by filtration and washed with CH₂Cl₂ and dried under highvacuum to produce a gray solid (2.245 g, 99.5%). ¹H NMR (DMSO-d₆) δ 9.5(br, 2H), 8.76 (s, 1H), 8.70 (d, 1H), 8.1 (dd, 1H), 8.08 (d, 1H), 7.80(d, 2H), 7.55 (d, 2H), 6.53 (s, 1H), 4.37 (q, 2H), 1.36 (t, 3H), 1.30(s, 9H); LC-MS: ESI 504 (M+H)⁺.

D. The intermediate from Step C underwent base hydrolysis as describedin Example 10F to produce the carboxylic acid.

E. Sodium2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylatewas prepared in the manner described in Example 9B, using the compoundfrom Step D; ¹H NMR (DMSO-d₆) δ 8.67 (s, 1H), 8.47 (d, 1H), 8.10 (dd,1H), 8.87 (d, 1H), 7.78 (d, 2H), 7.67 (d, 2H), 6.55 (s, 1H), 1.31 (s,9H); LC-MS: ESI 476 (M+H)⁺. [Compound C27]

Example 12 Preparation ofN-(5-tert-Butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)-3-oxo-propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea[Compound C5]

A. To a solution of3-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoicacid from Example 10F (0.310 g, 0.61 mmol) in DMF (8 mL) at roomtemperature was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.173 g, 0.9 mmol) and 1-hydroxybenzotriazole hydrate(0.122 g, 0.9 mmol). After stirring 1 hour, 1-ethylpiperazine (0.5 mL)was added and the mixture was stirred at room temperature over night.The reaction was quenched with 60 mL water, the precipitate wascollected by filtration, washed with water and ether, and dried undervacuum with P₂O₅ to give the product as a white solid (0.174 g, 48%). ¹HNMR (CDCl₃) δ 9.54 (s, 1H), 8.88 (s, 1H), 8.65 (s, 1H), 7.88 (s, 1H),7.85 (d, 1H), 7.79 (d, 2H), 7.52 (d, 2H), 7.45 (d, 1H), 6.50 (s, 1H),3.49 (m, 6H, overlapping with solvent), 2.89 (m, 2H), 2.71 (m, 2H), 2.25(m, 4H), 1.30 (s, 9H), 0.97 (t, 3H); LC-MS: ESI 600 (M+H)⁺.

B. To prepare its hydrochloride salt, the product in Step A was treatedin the manner described in Example 3F. ¹H NMR (DMSO-d₆) δ 10.85 (br,1H), 9.69 (br, 1H), 9.41 (br, 1H), 8.71 (s, 1H), 7.88 (d and s, 2H),7.73 (d, 2H), 7.51 (d, 2H), 7.45 (d, 1H), 6.47 (s, 1H), 4.41 (m, 2H),4.05 (m, 1H), 3.35 (m, 3H), 2.69-3.10 (m, 8H), 1.24 (s, 9H), 1.17 (t,3H).

C. The following compounds were made in a manner similar to Step A, butreplacing 1-ethylpiperazine with other amines such as piperidine,morpholine and N,N-diethylamine. The corresponding hydrochloride saltwas prepared in the same manner as described in step B.

N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(3-oxo-3-piperidin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;(0.381 g, 84%). ¹H NMR (DMSO-d₆) δ 9.65 (s, 1H), 9.00 (s, 1H), 8.65 (s,1H), 7.90 (s, 1H), 7.86 (d, 1H), 7.78 (d, 2H), 7.54 (d, 2H), 7.46 (d,1H), 6.53 (s, 1H), 3.41 (m, 4H), 2.93 (t, 2H), 2.68 (t, 2H), 1.54 (m,2H), 1.42 (m, 4H), 1.30 (s, 9H); LC-MS: ESI 571 (M+H)⁺; [Compound C6]

N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(3-morpholino-4-yl-3-oxo-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;¹H NMR (DMSO-d₆) δ 9.56 (s, 1H), 8.90 (s, 1H), 8.66 (s, 1H), 7.89 (s,1H), 7.85 (d, 1H), 7.79 (d, 2H), 7.52 (d, 2H), 7.45 (d, 1H), 6.52 (s,1H), 3.52 (m, 4H), 3.50 (m, 4H), 2.94 (t, 2H), 2.70 (t, 2H), 1.30 (s,9H); LC-MS: ESI 573 (M+H)⁺; [Compound C7]

3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N,N-diethyl-propionamide;¹H NMR (DMSO-d₆) δ 9.7 (br, 1H), 9.23 (br, 1H), 8.65 (s, 1H), 7.87 (dand s, 2H), 7.76 (d, 2H), 7.53 (d, 2H), 7.45 (d, 1H), 6.52 (s, 1H), 3.25(m, 6H), 2.94 (m, 2H), 2.65 (m, 2H), 1.30 (s, 9H), 1.02 (m, 6H);[Compound C8]

3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-morpholin-4-yl-ethyl)-propionamidehydrochloride; ¹H NMR (DMSO-d₆) δ 10.6 (br, 1H), 9.61 (br, 1H), 9.17(br, 1H), 8.64 (s, 1H), 8.20 (t, 1H), 7.82 (d and s, 2H), 7.71 (d, 2H),7.48 (d, 2H), 7.36 (d, 1H), 6.46 (s, 1H), 3.86 (m, 2H), 3.71 (t, 2H),3.77 (m, 4H), 2.88-3.07 (m, 6H), 2.45 (m, 2H), 1.23 (s, 9H); [CompoundC9]

3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-piperidin-1-yl-ethyl)-propionamidehydrochloride; ¹H NMR (DMSO-d₆) δ 10.04 (br, 1H), 9.70 (br, 1H), 9.36(br, 1H), 8.72 (s, 1H), 8.29 (t, 1H), 7.88 (d and s, 2H), 7.76 (d, 2H),7.53 (d, 2H), 7.42 (d, 1H), 6.50 (s, 1H), 3.39 (m, 4H), 3.95 (m, 4H),2.77 (m, 2H), 2.47 (m, 2H), 1.69 (m, 5H), 1.27 (s and m, 10H); [CompoundC10]

3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)-propionamidehydrochloride; ¹H NMR (DMSO-d₆) δ 10.4 (br, 1H), 9.71 (br, 1H), 9.34(br, 1H), 8.73 (s, 1H), 8.26 (t, 1H), 7.90 (d and s, 2H), 7.78 (d, 2H),7.55 (d, 2H), 7.45 (d, 1H), 6.53 (s, 1H), 3.52 (m, 2H), 3.40 (m, 2H),3.15 (m, 2H), 2.8-3.00 (m, 4H), 2.5 (2H), 1.93 (m, 2H), 1.85 (m, 2H),1.30 (s, 9H); [Compound C11]; and

3-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-diethylamino-ethyl)-propionamidehydrochloride; ¹H NMR (DMSO-d₆) δ 9.95 (br, 1H), 9.64 (br, 1H), 9.25(br, 1H), 8.66 (s, 1H), 8.23 (t, 1H), 7.83 (d and s, 2H), 7.72 (d, 2H),7.48 (d, 2H), 7.38 (d, 1H), 6.46 (s, 1H), 3.34 (m, 2H), 2.88-3.07 (m,8H), 2.5 (2H), 1.24 (s, 9H), 1.10 (t, 6H) [Compound C12].

D. The following compounds were made in a manner similar to Step A, butreplacing the propanoic acid with3-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}aceticacid from Example 9A and using the appropriately substituted amines. Thecorresponding hydrochloride salts were prepared in the manner describedin Example 3F.

2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-morpholin-4-yl-ethyl)-acetamidehydrochloride; ¹H NMR (DMSO-d₆) δ 10.76 (br, 1H), 9.65 (br, 1H), 9.24(br, 1H), 8.70 (s, 1H), 8.51 (br, 1H), 7.91 (d and s, 2H), 7.76 (d, 2H),7.50 (m, 3H), 6.50 (s, 1H), 3.90 (m, 2H), 3.76 (t, 2H), 3.59 (s, 2H),3.40 (m, 4H), 3.14 (m. 2H), 2.99 (m, 2H), 1.27 (s, 9H); [Compound C13]

2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-piperidin-1-yl-ethyl)-acetamidehydrochloride; ¹H NMR (DMSO-d₆) δ 9.8 (br, 1H), 9.60 (br, 1H), 9.15 (br,1H), 8.64 (s, 1H), 8.47 (t, 1H), 7.86 (d and s, 2H), 7.72 (d, 2H), 7.48(d, 2H), 7.42 (d, 1H), 6.46 (s, 1H), 3.54 (s, 2H), 3.37 (m, 4H), 3.05(m, 2H), 2.81 (m, 2H), 1.64 (m. 6H), 1.24 (s, 9H); [Compound C14]

2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)-acetamidehydrochloride; ¹H NMR (DMSO-d₆) δ 9.95 (br, 1H), 9.70 (br, 1H), 9.26(br, 1H), 8.67 (s, 1H), 8.35 (t, 1H), 7.90 (d and s, 2H), 7.78 (d, 2H),7.54 (d, 2H), 7.46 (d, 1H), 6.53 (s, 1H), 3.59 (s, 2H), 3.34 (2H), 2.86(m, 6H), 1.80 (m, 4H), 1.30 (s, 9H); [Compound C15]

2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-diethylamino-ethyl)-acetamidehydrochloride; ¹H NMR (DMSO-d₆) δ 9.85 (br, 1H), 9.65 (br, 1H), 9.18(br, 1H), 8.70 (s, 1H), 8.49 (t, 1H), 7.93 (d and s, 2H), 7.79 (d, 2H),7.54 (d, 2H), 7.48 (d, 1H), 6.53 (s, 1H), 3.61 (s, 2H), 3.43 (m, 2H),3.14 (m, 6H), 1.30 (s, 9H), 1.18 (t, 6H); [Compound C16], and

1-(5-tert-butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethyl]benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-ureahydrochloride; ¹H NMR (DMSO-d₆) δ 10.9 (br, 1H), 9.78 (br, 1H), 9.40(br, 1H), 8.81 (s, 1H), 8.01 (d, 1H), 7.95 (s, 1H), 7.86 (d, 2H), 7.63(d, 2H), 7.50 (d, 1H), 6.60 (s, 1H), 4.55 (d, 1H), 4.3 (d, 1H), 4.00 (s,2H), 3.57 (m, 3H), 3.21 (m, 3H), 3.00 (m, 2H), 1.37 (s, 9H), 1.35 (t,3H); [Compound C17]; and

1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-morpholin-4-yl-2-oxo-ethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-urea;¹H NMR (DMSO-d₆) δ 9.55 (s, 1H), 8.88 (s, 1H), 8.66 (s, 1H), 7.88 (d,1H), 7.85 (s, 1H), 7.78 (d, 2H), 7.53 (d, 2H), 7.41 (dd, 1H), 6.53 (s,1H), 3.86 (s, 2H), 3.55 (m, 6H), 3.47 (m, 2H), 1.30 (s, 9H) [CompoundC18].

E. The following compounds were made in a manner similar to Step A, butreplacing the propanoic acid with2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylicacid from Example 11D and using the appropriately substituted amines.The corresponding hydrochloride salts were prepared in the mannerdescribed in Example 3F.

2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}imidazo[2,1-b][1,3]benzothiazole-7-carboxylicacid (2-morpholin-4-yl-ethyl)-amide hydrochloride; ¹H NMR (DMSO-d₆) δ10.5 (br, 1H), 9.65 (s, 1H), 9.17 (s, 1H), 9.02 (t, 1H), 8.76 (s, 1H),8.59 (s, 1H), 8.09 (m, 2H), 7.79 (d, 2H), 7.56 (d, 2H), 6.53 (s, 1H),4.00 (m, 2H), 3.82 (m, 4H), 3.57 (m, 2H), 3.35 (m, 2H), 3.17 (m, 2H),1.31 (s, 9H); LC-MS: ESI 588 (M+H)⁺; [Compound C19];

2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-imidazo[2,1-b][1,3]benzothiazole-7-carboxylicAcid (2-Piperidin-1-yl-ethyl)-amide hydrochloride ¹H NMR (DMSO-d₆) δ 9.8(br, 1H), 9.66 (s, 1H), 9.20 (s, 1H), 9.03 (t, 1H), 8.76 (s, 1H), 8.59(d, 1H), 8.09 (m, 2H), 7.79 (d, 2H), 7.56 (d, 2H), 6.53 (s, 1H), 3.72(m, 2H), 3.56 (m, 2H), 3.26 (m, 2H), 2.96 (m, 2H), 1.80 (m, 5H), 1.4 (m,1H), 1.30 (s, 9H); LC-MS: ESI 586 (M+H)⁺; [Compound C20];

2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-imidazo[2,1-b][1,3]benzothiazole-7-carboxylicAcid (2-Pyrrolidin-1-yl-ethyl)-amide hydrochloride, ¹H NMR (DMSO-d₆) δ10.2 (br, 1H), 9.68 (s, 1H), 9.24 (s, 1H), 8.99 (t, 1H), 8.77 (s, 1H),8.60 (d, 1H), 8.09 (m, 2H), 7.79 (d, 2H), 7.56 (d, 2H), 6.53 (s, 1H),3.67 (m, 4H), 3.37 (m, 2H), 3.06 (m, 2H), 2.00 (m, 4H), 1.31 (s, 9H);LC-MS: ESI 572 (M+H)⁺; [Compound C21];

2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-imidazo[2,1-b][1,3]benzothiazole-7-carboxylicacid (2-diethylamino-ethyl)-amide hydrochloride; ¹H NMR (DMSO-d₆) δ 9.8(br, 1H), 9.62 (s, 1H), 9.13 (s, 1H), 8.98 (t, 1H), 8.74 (s, 1H), 8.55(d, 1H), 8.07 (m, 2H), 7.77 (d, 2H), 7.53 (d, 2H), 6.51 (s, 1H), 3.66(m, 2H), 3.22 (m, 6H), 1.28 (s, 9H), 1.22 (t, 6H); LC-MS: ESI 574(M+H)⁺; [Compound C22];

1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-ethyl-piperazine-1-carbonyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-ureahydrochloride; ¹H NMR (DMSO-d₆) δ 10.7 (br, 1H), 9.73 (s, 1H), 9.27 (s,1H), 8.84 (s, 1H), 8.27 (s, 1H), 8.12 (d, 1H), 7.86 (d, 2H), 7.76 (d,1H), 7.64 (d, 2H), 6.60 (s, 1H), 3.54 (m, 4H), 3.16 (m, 6H), 1.37 (s,9H), 1.33 (t, 3H); LC-MS: ESI 572 (M+H)⁺; [Compound C23];

1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(piperazine-1-carbonyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-ureahydrochloride, ¹H NMR (DMSO-d₆) δ 9.63 (s, 1H), 9.10 (s, 1H), 9.06 (br,2H), 8.76 (s, 1H), 8.19 (s, 1H), 8.04 (d, 1H), 7.80 (d, 2H), 7.69 (d,1H), 7.55 (d, 2H), 6.52 (s, 1H), 3.73 (m, 4H), 3.21 (m, 4H), 1.30 (s,9H); LC-MS: ESI 544 (M+H)⁺, [Compound C24]; and

1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazine-1-carbonyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-ureahydrochloride, ¹H NMR (DMSO-d₆) δ 10.8 (br, 1H), 9.63 (s, 1H), 9.22 (s,1H), 8.72 (s, 1H), 8.13 (s, 1H), 8.00 (d, 1H), 7.72 (d, 2H), 7.62 (d,1H), 7.49 (d, 2H), 6.46 (s, 1H), 3.33 (m, 4H), 3.06 (m, 4H), 2.74 (s,3H), 1.24 (s, 9H); LC-MS. ESI 558 (M+H)⁺ [Compound C25].

Example 13 Preparation ofN-(5-tert-Butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)ureaHydrochloride [Compound D1]

To a suspension ofN-(5-tert-butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)-3-oxo-propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)ureafrom Example 12A (0.17 g, 0.28 mmol) in THF (10 mL) at room temperaturewas added 2.0 M solution of BH₃/Me₂S in THF (1 mL). The mixture washeated to reflux for 4 hours. The reaction was quenched by dropwiseaddition of 10% HCl solution and stirred at room temperature for 15 min.The mixture was basified with saturated NaHCO₃ solution and wasextracted with dichloromethane. The combined organic extracts were driedover MgSO₄ and concentrated. The crude product was purified by Flashchromatography with silica gel using a 30-100% hexane/ethyl acetategradient followed by a 0-20% methanol/ethyl acetate gradient. Theappropriate fractions were collected, combined, and concentrated to givefree base,N-(5-tert-butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea.The free base was dissolved in dichloromethane (about 1 mL) and methanol(a few drops). To this solution was added dropwise a 1.0 M solution ofHCl/ether (1.3 equivalents) and a precipitate was formed. Afterevaporation of the solvents, the residue was taken up in ether,filtered, and washed with ether to give the product as a white solid(0.011 g, 6%). ¹H NMR (DMSO-d₆) δ 9.6 (s, 1H), 9.07 (s, 1H), 8.69 (s,1H), 7.92 (m, 2H), 7.78 (d, 2H), 7.54 (d, 2H), 7.48 (d, 1H), 6.53 (s,1H), 3.50 (4H, overlapping with solvent), 3.22 (m, 6H), 2.75 (m, 4H),2.10 (m, 2H), 1.30 (s, 9H), 1.24 (t, 3H); LC-MS: ESI 586 (M+H)⁺.

Example 14 Preparation of3-(5-tert-Butyl-isoxazol-3-yl)-1-methyl-1-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea[compound D2] and1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea[Compound D3]

A. To a suspension ofN-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(3-morpholino-4-yl-3-oxo-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea(0.38 g, 0.66 mmol) from Example 12C in THF (10 mL) at room temperaturewas dropped 2.0 M solution of BH₃/Me₂S in THF (1.5 mL). The reactionmixture was heated to reflux overnight. To the mixture was added 10% HClsolution to destroy excess BH₃/Me₂S, quenched with CH₂Cl₂, neutralizedwith saturated NaHCO₃ solution. The organic layer was dried over MgSO₄and concentrated to give a mixture of two compounds;methyl-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amineand4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenylamine.

B. To the mixture was added toluene and5-tert-butyl-3-isocyanato-isoxazole (150 mg) and heated at 110° C.overnight. It was quenched with CH₂Cl₂ and saturated NaHCO₃ solution.The organic layer was dried over MgSO₄ and concentrated. The crudemixture was separated by Flash chromatography with 0-10% MeOH/CH₂Cl₂ aseluant to give two compounds:3-(5-tert-butyl-isoxazol-3-yl)-1-methyl-1-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureaand1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea.

C. The corresponding hydrochloride salts were prepared in a mannerdescribed in Example 3F:

3-(5-tert-Butyl-isoxazol-3-yl)-1-methyl-1-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureahydrochloride; ¹H NMR (DMSO-d₆) δ 10.7 (br, 1H), 9.31 (br, 1H), 8.81 (s,1H), 7.94 (m, 2H), 7.88 (d, 2H), 7.49 (m, 1H), 7.38 (d, 2H), 6.50 (s,1H), 3.94 (m, 2H), 3.76 (m, 6H), 3.30 (s, 3H), 3.09 (m, 4H), 2.77 (m,4H), 2.08 (m, 2H), 1.28 (s, 9H); and1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-ureahydrochloride; ¹H NMR (DMSO-d₆) δ 10.4 (br, 1H), 9.64 (br, 1H), 9.1 (br,1H), 8.70 (s, 1H), 7.91 (d and s, 2H), 7.79 (d, 2H), 7.54 (d, 2H), 7.45(d, 1H), 6.53 (s, 1H), 3.93 (m, 2H), 3.73 (m, 6H), 3.09 (m, 4H), 2.78(m, 4H), 2.1 (m, 2H), 1.30 (s, 9H).

Example 15 Preparation ofN-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(3-piperidin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}ureaHydrochloride [Compound D4]

To a suspension ofN-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(3-oxo-3-piperidin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}ureafrom Example 12C (0.36 g, 0.63 mmol) in THF (10 mL) at room temperaturewas added 1.0 M solution of BH₃/THF in THF (10 mL). The mixture washeated to reflux over night, but LC-MS showed the reaction was notcomplete. Therefore, additional 5.0 mL of 1.0 M BH₃/THF solution wasadded and heated to reflux for 8 hours. The reaction was quenched bydropwise addition of 10% HCl solution and stirred at room temperaturefor 20 min. The mixture was basified with saturated NaHCO₃ solution andextracted with dichloromethane. The combined organic extracts were driedover MgSO₄ and concentrated. The crude product was purified by Flashchromatography with silica gel using a 0-10% methanol/dichloromethanegradient. The appropriate fractions were collected, combined, andconcentrated to give free base,N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(3-piperidzin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea(0.182 g). ¹H NMR (DMSO-d₆) δ 9.54 (s, 1H), 8.88 (s, 1H), 8.67 (s, 1H),7.90 (s, 1H), 7.88 (d, 1H), 7.79 (d, 2H), 7.53 (d, 2H), 7.45 (d, 1H),6.53 (s, 1H), 2.75 (m, 8H), 2.05 (m, 2H), 1.67 (m, 2H), 1.47 (m, 4H),1.30 (s, 9H); ¹³C NMR (DMSO-d₆) δ 180.55, 158.75, 151.65, 146.97,146.42, 138.99, 138.38, 130.52, 129.59, 128.77, 127.27, 125.58, 124.70,119.05, 113.37, 108.58, 92.81, 65.28, 57.96, 32.90, 28.72, 24.93, 22.55,20.24, 15.53; LC-MS: ESI 557 (M+H)⁺.

The free base was dissolved in 2 mL dichloromethane and 0.5 mL methanol.A 1.0 M solution of HCl/ether (0.4 mL, 1.2 equivalent) was addeddropwise. After standing for several minutes, a white solid was formed,collected by filtration, washed with ether, and dried under vacuum togive the product as a white solid (0.120 g, 32%).

¹H NMR (DMSO-d₆) δ 9.6 (s, 1H), 9.05 (s, 1H), 8.70 (s, 1H), 7.92 (s,1H), 7.9 (d, 1H), 7.78 (d, 2H), 7.55 (d, 2H), 7.45 (d, 1H), 6.53 (s,1H), 2.74 (m, 8H), 2.05 (m, 2H), 1.65 (m, 2H), 1.5 (m, 4H), 1.30 (s,9H); LC-MS: ESI 557 (M+H)⁺.

Example 16 Preparation of1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-morpholin-4-yl-ethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-ureaHydrochloride [Compound D5]

A. Preparation of the intermediate methyl[2-(4-nitro-phenyl)-imidazo[2,1-b][1,3]benzothiazol-7-yl]-acetic acid:To a suspension of methyl[2-(4-Nitrophenyl)imidazo[2,1-b][1,3]benzothiazol-7-yl]acetate fromExample 8C (4.51 g, 12.28 mmol) in THF (60 mL) was added LiOH.H₂O (2.727g, 65 mmol) and water (30 mL). The mixture was stirred at roomtemperature for two hours. After removal of THF, the aqueous phase wasacidified with 10% HCl solution to pH 6. A yellow solid was collected bytrituration, and washed with water and dried under high vacuum with P₂O₅(4.249 g, 98%). ¹H NMR (DMSO-d₆) δ 9.02 (s, 1H), 8.27 (d, 2H), 8.09 (d,2H), 8.88 (s and d, 2H), 7.43 (d, 1H), 3.56 (s, 2H).

B. Preparation of the intermediate1-morpholin-4-yl-2-[2-(4-nitro-phenyl)-imidazo[2,1-b][1,3]benzothiazol-7-yl]-ethanone:To the intermediate from step A (883 mg, 2.5 mmol) in DMF (14 mL) atroom temperature was addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.767 g, 4mmol) and 1-hydroxybenzotriazole hydrate (0.540 g, 4 mmol). Afterstirring for 30 minutes, morpholine (1 mL) was added and stirred at roomtemperature for 5 hours. The reaction was quenched with 100 mL of water,and the precipitate was collected by filtration, washed with water anddried under vacuum with P₂O₅ to give a yellow solid (0.908 g, 86%). ¹HNMR (DMSO-d₆) δ 9.05 (s, 1H), 8.31 (d, 2H), 8.12 (d, 2H), 7.94 (d, 1H),7.88 (s, 1H), 7.43 (d, 1H), 3.87 (s, 2H), 3.56 (m, 6H), 3.48 (m, 2H).

C. To prepare the intermediate4-[7-(2-morpholin-4-yl-ethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenylamine:to a suspension of1-morpholin-4-yl-2-[2-(4-nitro-phenyl)-benzo[d]imidazo[2,1-b]thiazol-7-yl]-ethanone(0.905 g, 2.14 mmol) in THF (30 mL) at room temperature was dropped a2.0 M solution of BH₃-Me₂S in THF (5 mL), and then it was heated at 90°C. for 4 hours. To the reaction was carefully dropped 10% HCl (15 mL)and stirred at room temperature for 10 minutes. It was neutralized withsaturated NaHCO₃ and extracted with CH₂Cl₂. Extracts were combined,dried over MgSO₄, and concentrated to give a yellow solid.

The yellow solid was suspended in methanol (30 mL) and to it was addedRaney nickel (˜1.0 g wet). The reaction mixture was shacked underhydrogen (50 psi) for 6 hours. It was filtered with Celite and washedwith methanol. The filtration was concentrated to give the product as asolid. ¹H NMR (DMSO-d₆) δ 8.40 (s, 1H), 7.85 (s, 1H), 7.82 (d, 1H), 7.52(d, 2H), 7.40 (d, 1H), 6.61 (d, 2H), 5.19 (s, 2H), 3.58 (t, 4H), 2.85(t, 2H), 2.56 (t, 2H), 2.43 (t, 4H).

D. The coupling reaction was performed in the manner described inExample 3E to form the title product and its hydrochloride salt wasprepared in the manner described in Example 3F; ¹H NMR (DMSO-d₆) δ 10.8(br, 1H), 9.66 (s, 1H), 9.20 (s, 1H), 8.71 (s, 1H), 7.97 (d and s, 2H),7.79 (d, 2H), 7.55 (d, 2H), 7.49 (d, 1H), 6.53 (s, 1H), 4.01 (m, 2H),3.77 (t, 2H), 3.54 (t, 2H), 3.41 (m, 2H), 3.18 (m, 4H), 1.30 (s, 9H);LC-MS: ESI 545 (M+H)⁺.

E. The following compounds were made in the manner described in StepsA-D above, using the appropriate amine in Step B:

1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-piperidin-1-yl-ethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-ureahydrochloride: ¹H NMR (DMSO-d₆) δ 10.0 (br, 1H), 9.68 (s, 1H), 9.24 (s,1H), 8.71 (s, 1H), 7.96 (d and s, 2H), 7.78 (d, 2H), 7.55 (d, 2H), 7.49(d, 1H), 6.53 (s, 1H), 3.52 (m, 2H), 3.33 (m, 2H), 3.17 (m, 2H), 2.92(m, 2H), 1.77 (m, 5H), 1.45 (m, 1H), 1.30 (s, 9H); LC-MS: ESI 544(M+H)⁺. [Compound D6]

1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-ethyl-piperazin-1-yl)-ethyl]-imidazo[2,1-b][1,3]benzothiazol-2-yl}-phenyl)-ureahydrochloride: ¹H NMR (DMSO-d₆) δ 11.3 (br, 1H), 9.64 (s, 1H), 9.14 (s,1H), 8.69 (s, 1H), 7.96 (d and s, 2H), 7.78 (d, 2H), 7.51 (m, 3H), 6.52(s, 1H), 3.75 (m, 4H), 3.21 (m, 6H), 2.53 (m, 4H), 1.30 (s, 9H), 1.27(t, 3H); LC-MS: ESI 573 (M+H)⁺. [Compound D7]

F. The following compounds were prepared in the manner described inSteps A-D above, except that at Step C, a two-step reduction was carriedout in which the reduction of the nitro group occurred first usingSnCl₂.H₂0 in ethanol heated to reflux for up to several hours. Thisreaction was followed by a second reduction of the amide to the tertiaryamine with BH₃-Me₂S in THF.

1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-morpholin-4-ylmethyl-imidazo[2,1-b][1,3]benzothiazol-2-yl)-phenyl]-ureahydrochloride; ¹H NMR (DMSO-d₆) δ 10.7 (br, 1H), 9.58 (s, 1H), 9.09 (s,1H), 8.68 (s, 1H), 8.12 (s, 1H), 8.01 (d, 1H), 7.73 (m, 3H), 7.48 (d,2H), 6.46 (s, 1H), 4.39 (s, 2H), 3.88 (m, 2H), 3.66 (m, 2H), 3.22 (m,2H), 3.10 (m, 2H), 1.24 (s, 9H); LC-MS: ESI 531 (M+H)⁺. [Compound D8]

1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(4-ethyl-piperazin-1-ylmethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-ureahydrochloride: ¹H NMR (DMSO-d₆) δ 11.5 (br, 1H), 9.71 (s, 1H), 9.32 (s,1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.06 (d, 1H), 7.82 (m, 3H), 7.56 (d,2H), 6.53 (s, 1H), 4.39 (s, 2H), 3.65 (m, 4H), 3.38 (m, 4H), 3.15 (m,2H), 1.30 (s, 9H), 1.22 (t, 3H); LC-MS: ESI 559 (M+H)⁺. [Compound D9]

1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-piperidin-1-ylmethyl-imidazo[2,1-b][1,3]benzothiazol-2-yl)-phenyl]-ureahydrochloride: ¹H NMR (DMSO-d₆) δ 10.5 (br, 1H), 9.79 (s, 1H), 9.44 (s,1H), 8.83 (s, 1H), 8.29 (s, 1H), 8.13 (d, 1H), 7.87 (d and s, 3H), 7.62(d, 2H), 6.60 (s, 1H), 4.44 (s, 2H), 3.40 (m, 2H), 2.95 (m, 2H), 1.84(m, 5H), 1.45 (m, 1H), 1.37 (s, 9H); LC-MS: ESI 529 (M+H)⁺. [CompoundD10]

Example 17 Preparation of Morpholine-4-carboxylic acid{4-[7-(3-morpholin-4-yl-3-oxo-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide[Compound E1]

A. to a suspension of3-{2-[4-({[(5-tert-butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoicacid (0.504 g, 1 mmol) in CH₂Cl₂ was added 1.0 M solution of oxalylchloride in CH₂Cl₂ (2 mL), and followed by several drops of DMF. Afterit was stirred at room temperature for 2 hours, solvent was evaporated.To the residue was added CH₂Cl₂ and morpholine (2 mL) and the mixturewas stirred at room temperature for 2 hours. The reaction was quenchedwith water and CH₂Cl₂, basified with saturated NaHCO₃ solution, andextracted three times with CH₂Cl₂. The extracts were combined, driedover MgSO₄, and concentrated. The crude product was purified by Flashchromatography with 0-10% MeOH/EtOAc as eluant to give the product aswhite solid (0.126 g). ¹H NMR (DMSO-d₆) δ 8.61 (s, 2H), 7.89 (s, 1H),7.86 (d, 1H), 7.73 (d, 2H), 7.53 (d, 2H), 7.45 (d, 1H), 3.62 (m, 4H),3.50 (m, 4H), 3.44 (m, 8H), 2.94 (m, 2H), 2.70 (m, 2H).

Example 18 Preparation of2-benzo[d]isoxazol-3-yl-n-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-acetamide

A. Benzo[d]isoxazol-3-yl-acetic acid (0.260 g, 1.47 mmol) was dissolvedin 10 mL of dry DMF. To this solution was added HOBt(1-hydroxybenzotriazole hydrate, 0.238 g, 1.76 mmol) and EDCI(N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 0.338 g,1.76 mmol). After 20 minutes triethylamine (0.354 g, 0.487 mL, 3.5 mmol)was added followed by the addition of the amine intermediate fromExample 3D (0.394 g, 1.50 mmol), the reaction was allowed to stirovernight at room temperature. The solution was then poured into brine,and extracted with ethyl acetate and then CH₂Cl₂. The combined extractswere dried over magnesium sulfate, filtered and concentrated to a solid.This was purified using silica gel chromatography, with a gradient of0-10% methanol in CH₂Cl₂. containing 0.1% triethylamine. The appropriatefractions were collected and concentrated. The solid recrystallized frommethanol, CH₂Cl₂, ethyl acetate. The resulting solid collected byfiltration, and dissolved in methanol —CH₂Cl₂.

B. To this solution from Step A was added 3 mL of 4M HCl/dioxane, andthe resulting solution concentrated to a solid. This solid was dissolvedin 3 mL of methanol and ethyl ether added until a precipitate formed.This solid was collected by filtration, dried under high vacuum, to give72 mg of the hydrochloride salt; ¹H NMR (CDCl₃) 7.8 (m, 3H); 7.6 (m,5H); 4.2 (m, 4H); 3.8 (m, 2H); 3.2 (s, 3H); 3.0 (s, 3H); 3.9 (m, 1H);2.7 (m, 2H). [Compound E2]

C. The following compounds were prepared in the manner described in StepA using the appropriately substituted carboxylic acid in place of theacetic acid:

2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide;¹H NMR (CDCl₃) 7.8 (m, 3H); 7.6 (m, 2H); 7.4 (d, 1H); 6.9 (d, 1H); 4.3(m, 2H); 3.8 (m, 2H); 3.1 (m, 2H); 2.9 (m, 2H); and [Compound E3]

2-(4-chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide;¹H NMR (CDCl₃) 7.8 (m, 2H); 7.9 (s, 1H); 7.8 (d, 1H); 7.7 (d, 1H);7.7-7.4 (m, 6H); 7.4 (d, 1H); 7.0 (m, 1H); 4.3 (m, 2H); 3.8 (m, 5H); 3.0(m, 3H); 2.7 (m, 5H). [Compound E4]

Example 19 Preparation of1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;[Compound F1]

A. The title compound and the compounds listed in this Section A wereobtained using analogous procedures and reagents as described in Example3E using7-(2-morpholin-4-yl-ethoxy)-2-(4-amino-phenyl)imidazo[2,1-b][1,3]benzothiazoleand the appropriately substituted isocyanate:

Title compound: ¹H NMR (DMSO-d₆) 8.7 (s, 1H); 8.0 (d, 1H); 7.8 (m, 3H);7.5 (d, 2H); 7.3 (d, 1H); 7.1 (s, 1H); 6.8 (s, 2H); 4.4 (s, 2H); 4.3 (m,4H); 4.0 (m, 2H); 3.7 (m, 4H); 3.3 (m, 2H); [Compound F1]

1-(4-tert-Butyl-phenyl)-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;¹H NMR (DMSO-d₆) 11.3 (s, 1H); 9.4 (s, 1H); 9.2 (s, 1H); 8.8 (s, 1H);8.2 (d, 1H); 7.9 (s, 1H); 7.8 (d, 2H); 7.6 (d, 2H); 7.4 (d, 2H); 7.3 (d,2H); 4.5 (s, 2H); 3.2 (m, 2H); 1.3 (s, 9H); [Compound F2]1-benzo[1,3]dioxol-5-yl-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;¹H NMR (DMSO-d₆) 8.5 (m, 3H); 7.8-7.6 (m, 3H); 7.5 (m, 2H); 7.2 (m, 2H);6.9 (m, 2H); 5.9 (s, 2H); 4.3 (m, 2H); 3.5 (m, 5H); 2.7 (m, 5H);[Compound F3]

1-(2-methyl-benzothiazol-5-yl)-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;¹H NMR (methanol-d₄) 8.4 (s, 1H); 8.2 (s, 1H); 7.8 (m, 4H); 7.4 (m, 4H);7.1 (m, 1H); 4.2 (t, 2H); 3.7 (m, 5H); 2.9 (m, 2H); 2.8 (m, 4H); 1.2 (m,2H). [Compound F8]

Binding Constant (K_(d)) Measurements for Small-Molecule-KinaseInteractions

Methods for measuring binding affinities for interactions between smallmolecules and kinases including FLT3, KIT, p38, ABL, VEGFR (also KDR)and EGFR are described in Fabian et al (2005) Nature Biotechnology 23(3): 329-336, which is incorporated by reference herein. By testingacross a large class of protein kinases, specificity of the kinaseinhibitors provided herein is also determined. The components of theassays include various human kinases expressed as fusions to T7bacteriophage particles and immobilized ligands that bind to the ATPsite of the kinases. For the assay, phage-displayed kinases andimmobilized ATP site ligands are combined with the compound to betested. If the test compound binds the kinase, it competes with theimmobilized ligand and prevents binding to the solid support. If thetest compound does not bind the kinase, phage-displayed proteins arefree to bind to the solid support through the interaction between thekinase and the immobilized ligand. The results are read out byquantitating the amount of fusion protein bound to the solid support,which is accomplished by either traditional phage plaque assays or byquantitative PCR (qPCR) using the phage genome as a template. Todetermine the affinity of the interactions between a test molecule and akinase, the amount of phage-displayed kinase bound to the solid supportis quantitated as a function of test compound concentration. Theconcentration of test molecule that reduces the number of phage bound tothe solid support by 50% is equal to the K_(d) for the interactionbetween the kinase and the test molecule. Typically, data are collectedfor twelve concentrations of test compound and the resultant bindingcurve is fit to a non-cooperative binding isotherm to calculate K_(d).

Binding affinity values are shown in Table 1 below and are reported asfollows: “+” represents binding dissociation constant (Kd) value of1,000 nM or higher; “++” represents binding dissociation constant (Kd)value of 100 nM to 1,000 nM; “+++” for represents binding dissociationconstant (Kd) value of 10 nM to 100 nM; and “++++” represents bindingdissociation constant (Kd) value of less than 10 nM.

In Vivo Study

Representative compounds were tested in xenograft mouse model in orderto evaluate the in vivo activity at 1, 3 and 10 mg/kg against wellestablished subcutaneous MV4-11 tumors in female athymic nude mice.Xenograft were initiated from MV4-11 human leukemia cells cultured inIscove's Modified Dulbecco's medium supplemented with 10%heat-inactivated fetal bovine serum, 100 units/mL penicillin G, 100μg/mL streptomycin sulfate, 0.25 μg/mL amphotericin B, 2 mM glutamine,0.075% sodium bicarbonate, and 25 μg/mL gentamicin. Tumor cells weremaintained in humidified atmosphere of 95% air and 5% CO₂ at 37° C. Thecells were harvested during logarithmic phase growth and resuspended ata concentration of 5×10⁷ cells/mL in 50% Matrigel matrix (BDBiosciences) and 50% PBS. MV4-11 cells (1×10⁷) were implantedsubcutaneously into the right flank of each test mouse and the growth oftumors was monitored. Twelve days later, on Day 1 of the study, micewere placed in eight groups each consisting of ten mice with individualtumor sizes of 126 to 221 mm³ and group mean tumor size of 174 mm³,tumor volume calculated as a product of width×width×length in mm of anMV4-11 tumor. The test compounds were formulated for dosing at 10 mL/kgand were administered by oral gavage (p.o.) once daily for twenty-eightdays (qd×28). Each dose of drug was given in a volume of 0.2 mL per 20 gof body weight (10 mL/kg) and was adjusted for the body weight of theanimal. Each animal was sacrificed when its tumor reached thepredetermined endpoint size of 1000 mm³ or on the last day of the study(Day 59), whichever came first. The time to endpoint (TTE) for eachmouse was calculated from the following equation: TTE (days)=[log10(endpoint volume in mm³)−b]/m where b is the intercept and m is theslope of the line obtained by linear regression of a log transformedtumor growth data set. Treatment outcome was determined from tumorgrowth delay (TGD), defined as the increase in the median time toendpoint (TTE) in a treatment group compared to the control groupexpressed in days, or as a percentage of the median TTE of the controlgroup. FIG. 1 shows median tumor growth curves generated from the invivo experiment which demonstrates that a representative compoundprovided herein produces dose-dependent antitumor activity.

Cellular Proliferation Assay

Cancer cell viability and proliferation can be evaluated using atetrazolium salt reduction cell-based assay. In viable cells, thiscalorimetric assay can measure mitochondrial reduction of a tetrazoliumcomponent (MTS) into an insoluble formazan product.

MV4-11 is a well-characterized Flt3-dependent human cell line containinternal tandem duplications (ITD) found in patients with acute myeloidleukemia and which express constitutively active Flt3 receptors (Yee etal. Blood (2002) 100(8):2941-2949). This cell line was used to determinethe ability of the compounds provided herein to inhibit Flt3 in intactcells. The RS4-11 cell line, which expresses the wild-type (WT)receptor, is also used as a control to verify the test compound'sability to inhibit the FLT3 receptor containing the ITD mutation. MV4-11cell proliferation was measured after 72 hour incubation with thecompounds provided herein, and RS4-11 after 48 hour incubation with thecompounds provided herein, in both cases using a standard MTS protocol(Promega Cat #5430 “Cell Titer 96 Aqueous Non-radioactive CellProliferation Assay”).

MV4-11 cells were plated at 10,000 cells per well in DMEM medium with0.5% serum. RS4-11 cells were plated at 20,000 cells per well in RPMIwith 0.5% serum. The compound plate was set up by aliquoting into column1 of a 96 well 300 ul polypropylene plate, the negative control (DMSO),aliquoting into column 12 the positive control (an internal compoundpreviously shown to have an IC50 of 64 nM in the MV4-11 assay) andtitrating the test compound in serial dilutions into columns 2-11. Analiquot from each well of the compound plate was transferred to theplated cells and then incubated @ 37° C. in 5% CO₂ (for 3 days for theMV4-11 cells, 2 days for the RS4-11 cells).

MTS tetrazolium compound (Owen's reagent) was thawed in a H₂O bath. 20μl of MTS tetrazolium was added to each well of optical plate and thecells were incubated @ 37° C. in 5% CO₂ for 2 hours. The absorbancemeasured at 490 nm using Spectramax Plus 384 Absorbance MicroplateReader by Molecular Devices.

Cell proliferation values are measured in terms of concentration of testcompound that achieves 50% inhibition of cellular proliferation comparedto control (IC₅₀) and are reported in Tables 1 and 2 below as follows:“+” represents IC₅₀ values of less than 10 nM, “++” represents IC₅₀values of between 10 nM and 100 nM and “+++” represents IC₅₀ values ofgreater than 100 nM.

TABLE 1 Binding Binding Binding Assay Cellular Assay Assay AssayCompound FLT3 K_(d) MV-proliferation KIT K_(d) CSF1R K_(d) No. (nM) IC₅₀(nM) (nM) (nM) A1 ++++ + A2 +++ + A3 ++++ + A4 ++++ + A5 ++++ + A6++++ + A7 ++++ + B1 ++++ + ++++ +++ B2 ++++ + ++++ B3 ++++ + ++++ B4++++ + ++++ B5 ++++ + +++ +++ B6 ++++ + +++ B7 ++++ + +++ +++ B8 ++++ +++++ B9 ++++ + +++ B10 ++++ + +++ +++ B11 ++++ + +++ ++ B12 ++++ + +++ ++B13 ++ +++ + + B14 + +++ + + C1 ++++ + ++++ C2 ++++ + ++++ C3 ++++ ++++ + C4 ++++ + ++++ +++ C5 ++++ + ++++ +++ C7 ++++ + ++++ +++ C8 ++++ +++++ +++ C9 ++++ + ++++ ++++ C10 ++++ + ++++ +++ C11 ++++ + ++++ ++++C12 ++++ + ++++ +++ C13 ++++ + ++++ +++ C14 ++++ + ++++ +++ C15 ++++ +++++ +++

TABLE 2 Binding Binding Binding Assay Cellular Assay Assay AssayCompound FLT3 K_(d) MV-proliferation KIT K_(d) CSF1R K_(d) No. (nM) IC₅₀(nM) (nM) (nM) C16 ++++ + ++++ +++ C17 ++++ + ++++ +++ C18 ++++ + +++++++ C19 ++++ + ++++ +++ C20 ++++ + ++++ +++ C21 ++++ + ++++ +++ C22++++ + ++++ +++ C23 ++++ + ++++ +++ C24 ++++ + ++++ +++ C25 ++++ + +++++++ C26 ++++ + +++ ++ C27 ++++ + ++++ +++ D1 ++++ + ++++ D2 +++ ++ +++++++ D3 ++++ + ++++ +++ D4 ++++ + +++ +++ D5 ++++ + ++++ ++++ D6 ++++ +++++ ++++ D7 ++++ + ++++ ++++ D8 ++++ + ++++ +++ D9 ++++ + ++++ +++ D10++++ + ++++ +++ E1 ++ +++ + + E2 ++++ + +++ + E3 + +++ + + E4 +++ ++ ++++ F1 ++++ + ++++ ++ F2 ++++ + ++++ +++ F3 ++++ + ++++ + F8 ++++ + +++++

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the claimed subject matter and areencompassed by the appended claims.

1. A compound of formula (I),

wherein bond b is a single bond or double bond; X is —S—, —N(R⁵)— or—O—; Z¹ and Z³ are each independently —N(R⁵)—, —(CH₂)_(q)—, —O—, —S—, ora direct bond; Z² is —C(O)— or —C(S)—; m is an integer from 1 to 2; n isan integer from 1 to 3; each q is independently an integer from 1 to 4;R⁰ is hydrogen, halo, hydroxy, optionally substituted alkyl, oroptionally substituted alkoxy; each R¹ is independently selected fromthe group consisting of optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heteroaralkyl, optionallysubstituted heteroaralkenyl, —R⁶OR⁷, —R⁶SR⁷, —R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂,—R⁶—OR⁹OR⁷, —R⁶CN, —R⁶C(O)R⁷, —R⁶C(S)R⁷, —R⁶C(NR⁷)R⁷, —R⁶C(O)OR⁷,—R⁶C(S)OR⁷, —R⁶C(NR⁷)OR⁷, —R⁶C(O)N(R⁷)₂, —R⁶C(S)N(R⁷)₂, —R⁶C(NR⁷)N(R⁷)₂,—R⁶C(O)N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)SR⁸, —R⁶C(S)SR⁸, —R⁶C(NR⁷)SR⁸,—R⁶S(O)_(t)OR⁷, —R⁶S(O)_(t)N(R⁷)₂, —R⁶S(O)_(t)N(R⁷)N(R⁷)₂,—R⁶S(O)_(t)N(R⁷)N═C(R⁷)₂, —R⁶S(O)_(t)N(R⁷)C(O)R⁸,—R⁶S(O)_(t)N(R⁷)C(O)N(R⁷)₂, —R⁶S(O)_(t)N(R⁷)C(NR⁷)N(R⁷)₂,—R⁶N(R⁷)C(O)R⁸, —R⁶N(R⁷)C(O)OR⁸, —R⁶N(R⁷)C(O)SR⁸, —R⁶N(R⁷)C(NR⁷)SR⁸,—R⁶N(R⁷)C(S)SR⁸, —R⁶N(R⁷)C(O)N(R⁷)₂, —R⁶N(R⁷)C(NR⁷)N(R⁷)₂,—R⁶N(R⁷)C(S)N(R⁷)₂, —R⁶N(R⁷)S(O)_(t)R⁸, —R⁶OC(O)R⁸, —R⁶OC(NR⁷)R⁸,—R⁶OC(S)R⁸, —R⁶OC(O)OR⁸, —R⁶OC(NR⁷)OR⁸, —R⁶OC(S)OR⁸, —R⁶OC(O)SR⁸,—R⁶OC(O)N(R⁷)₂, —R⁶OC(NR⁷)N(R⁷)₂, —R⁶OC(S)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂,—R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)R⁹C(O)R⁷, —R⁶C(O)R⁹C(S)R⁷,—R⁶C(O)R⁹C(NR⁷)R⁷, —R⁶C(O)R⁹C(O)OR⁷, —R⁶C(O)R⁹C(S)OR⁷,—R⁶C(O)R⁹C(NR⁷)OR⁷, —R⁶C(O)R⁹C(O)N(R⁷)₂, —R⁶C(O)R⁹C(S)N(R⁷)₂,—R⁶C(O)R⁹C(NR⁷)N(R⁷)₂, —R⁶C(O)R⁹C(O)SR⁸, —R⁶C(O)R⁹C(S)SR⁸,—R⁶C(O)R⁹C(NR⁷)SR⁸, —R⁶OR⁹OR⁷, —R⁶C(O)R⁹N(R⁷)R⁹N(R⁷)₂,—R⁶C(O)R⁹N(R⁷)R⁹OR⁷ and —R⁶C(O)N(R⁷)R⁹OR⁷; t is 1 or 2; each R² isindependently selected from hydrogen, halo, nitro, cyano, optionallysubstituted alkyl, —OR¹², —SR¹², —N(R¹²)₂, —S(O)_(t)R¹³, —C(O)R¹²,—C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², and —N(R¹²)S(O)_(t)R¹³; R³ ishydrogen, halo, nitro, cyano, optionally substituted alkyl, —OR¹²,—SR¹², —N(R¹²)₂, —S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂,—C(O)SR¹², or —N(R¹²)S(O)_(t)R¹³; R⁴ is selected from the groupconsisting of optionally substituted alkyl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedcycloalkyl, optionally substituted cycloalkenyl, and optionallysubstituted aryl; each R⁵ is independently hydrogen, or optionallysubstituted alkyl; each R⁶ is independently a direct bond, an optionallysubstituted alkylene chain, or an optionally substituted alkenylenechain; each R⁷ is independently selected from (i) or (ii) below (i) R⁷is selected from a group consisting of hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroaralkyl, or (ii) two R⁷ groups together with the atomto which they are attached form an optionally substituted heterocyclylor optionally substituted heteroaryl; R⁸ is independently selected fromthe group consisting of optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroaralkyl; each R⁹ is independently an optionally substitutedalkylene chain or an optionally substituted alkenylene chain; each R¹²is independently selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl; and R¹³ is independently selectedfrom the group consisting of optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroaralkyl; with the proviso that, (i) if -Z¹Z²Z³R⁴ is —NHC(O)Bu thenR¹ may not be ethoxy; (ii) if -Z¹Z²Z³R⁴ is —C(O)OR_(p), where R_(p) ismethyl, or ethyl, then R¹ may not be hydroxyl, methoxy ormethoxycarbonyl; (iii) if -Z¹Z²Z³R⁴ is —NHC(O)C(O)OR_(p), where R_(p) ismethyl, or ethyl, then R¹ may not be methoxy; (iv) if -Z¹Z²Z³R⁴ is—CH₂C(O)OR_(p), where R_(p) is methyl, or ethyl, then R¹ may not bemethoxy or ethoxy; (v) if -Z¹Z²Z³R⁴ is —OC(O)CH₃, then R¹ may not bemethyl, methoxy or ethoxy; as a single stereoisomer, a mixture ofstereoisomers, a racemic mixture of stereoisomers, or as apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein the compound is of formula (I),


3. The compound of claim 1, wherein the compound is a pharmaceuticallyacceptable salt of the compound of formula (I).
 4. The compound of claim1, wherein R⁴ is optionally substituted heterocyclyl or optionallysubstituted heteroaryl.
 5. The compound of claim 1, wherein R⁴ isselected from

wherein, each R¹⁰ is independently selected from hydrogen, halo,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heterocyclyl andoptionally substituted heteroaryl.
 6. The compound of claim 4, whereinR⁴ is

wherein, each R¹⁰ is independently selected from hydrogen, halo,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heterocyclyl andoptionally substituted heteroaryl.
 7. The compound of claim 6, whereinR⁴ is

wherein R¹⁰ is hydrogen, alkyl, haloalkyl or haloaryl.
 8. The compoundof claim 7, wherein R¹⁰ is hydrogen, methyl, tert-butyl, trifluoromethylor p-chlorophenyl.
 9. The compound of claim 7, wherein R⁴ is


10. The compound of claim 1, wherein -Z¹Z²Z³- is —N(R⁵)C(O)N(R⁵)—,—N(R⁵)C(O)—, —C(O)N(R⁵)—, —OC(O)—, —C(O)O—, —N(R⁵)C(S)N(R⁵)—,—C(S)N(R⁵)—, —N(R⁵)C(S)—, —C(S)O— or —OC(S)— and each R⁵ isindependently hydrogen or optionally substituted alkyl.
 11. The compoundof claim 1, wherein R⁴Z³Z²Z¹- is R⁴N(R⁵)C(O)— or R⁴N(R⁵)C(S)—, and R⁵ ishydrogen, or optionally substituted alkyl.
 12. The compound of claim 10,wherein bond b is a double bond and X is —S—.
 13. The compound of claim12, wherein R⁴ is a five-membered or six-membered heteroaryl selectedfrom the group consisting of pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl and isothiazolyl.
 14. The compound of claim 13, wherein R¹ is

where K is —C(O)—, —(CH₂)_(q)—, —(CH₂)_(q)O—, —(CH₂)_(q)O(CH₂)_(q)—,—(CH₂)_(q)C(O)—, —C(O)NH(CH₂)_(q)—, —C(O)NH(CH₂)_(q)NH(CH₂)_(q)—,—(CH₂)_(q)C(O)NH(CH₂)_(q)—, —O(CH₂)_(q)—, —OC(O)—, —OC(O)(CH₂)_(q)— or adirect bond; Y is —O—; p is an integer 1; and each q is independently 2or
 3. 15. The compound of claim 14, wherein the compound is selectedfrom the group consisting of:2-Benzo[d]isoxazol-3-yl-N-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-acetamide;2-Methyl-4-trifluoromethyl-thiazole-5-carboxylic acid{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide;and 2-(4-Chloro-phenyl)-4-methyl-thiazole-5-carboxylic acid{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide.16. The compound of claim 4, wherein the compound ismorpholine-4-carboxylic acid{4-[7-(3-morpholin-4-yl-3-oxo-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-amide.17. The compound of claim 1, wherein R⁴Z³Z²Z¹- is R⁴N(R⁵)C(O)N(R⁵)— orR⁴N(R⁵)C(S)N(R⁵)—; and each R⁵ is independently hydrogen, or optionallysubstituted alkyl.
 18. A compound corresponding to formula (II):

wherein: X is —S—, —N(R⁵)— or —O—; X¹, X², X³, X⁴ are each independentlyselected from —C(R¹⁰)—, —C(R¹⁰)₂—, —N—, —N(R¹⁶)—, —O— and —S—, providedthat no more than two of X¹, X², X³ and X⁴ are heteroatoms and whereinno two adjacent X's are both —O— or —S—; and each R¹⁰ is independentlyselected from hydrogen, halo, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted heterocyclyl and optionally substituted heteroaryl; each R¹⁶is independently selected from hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heterocyclyl and optionally substitutedheteroaryl; n is an integer from 1 to 3; R⁰ is hydrogen, halo, hydroxy,optionally substituted alkyl, or optionally substituted alkoxy; each R¹is independently selected from the group consisting of halo, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally, substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheteroaralkyl, optionally substituted heteroaralkenyl, —R⁶OR⁷, —R⁶SR⁷,—R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂, —R⁶—OR⁹OR⁷, —R⁶CN, —R⁶C(O)R⁷, —R⁶C(S)R⁷,—R⁶C(NR⁷)R⁷, —R⁶C(O)OR⁷, —R⁶C(S)OR⁷, —R⁶C(NR⁷)OR⁷, —R⁶C(O)N(R⁷)₂,—R⁶C(S)N(R⁷)₂, —R⁶C(NR⁷)N(R⁷)₂, —R⁶C(O)N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)SR⁸,—R⁶C(S)SR⁸, —R⁶C(NR⁷)SR⁸, —R⁶S(O)_(t)OR⁷, —R⁶S(O)_(t)N(R⁷)₂,—R⁶S(O)_(t)N(R⁷)N(R⁷)₂, —R⁶S(O)_(t)N(R⁷)N═C(R⁷)₂,—R⁶S(O)_(t)N(R⁷)C(O)R⁸, —R⁶S(O)_(t)N(R⁷)C(O)N(R⁷)₂,—R⁶S(O)_(t)N(R⁷)C(NR⁷)N(R⁷)₂, —R⁶N(R⁷)C(O)R⁸, —R⁶N(R⁷)C(O)OR⁸,—R⁶N(R⁷)C(O)SR⁸, —R⁶N(R⁷)C(NR⁷)SR⁸, —R⁶N(R⁷)C(S)SR⁸, —R⁶N(R⁷)C(O)N(R⁷)₂,—R⁶N(R⁷)C(NR⁷)N(R⁷)₂, —R⁶N(R⁷)C(S)N(R⁷)₂, —R⁶N(R⁷)S(O)_(t)R⁸,—R⁶OC(O)R⁸, —R⁶OC(NR⁷)R⁸, —R⁶OC(S)R⁸, —R⁶OC(O)OR⁸, —R⁶OC(NR⁷)OR⁸,—R⁶OC(S)OR⁸, —R⁶OC(O)SR⁸, —R⁶OC(O)N(R⁷)₂, —R⁶OC(NR⁷)N(R⁷)₂,—R⁶OC(S)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂, —R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂,—R⁶C(O)R⁹C(O)R⁷, —R⁶C(O)R⁹C(S)R⁷, —R⁶C(O)R⁹C(NR⁷)R⁷, —R⁶C(O)R⁹C(O)OR⁷,—R⁶C(O)R⁹C(S)OR⁷, —R⁶C(O)R⁹C(NR⁷)OR⁷, —R⁶C(O)R⁹C(O)N(R⁷)₂,—R⁶C(O)R⁹C(S)N(R⁷)₂, —R⁶C(O)R⁹C(NR⁷)N(R⁷)₂, —R⁶C(O)R⁹C(O)SR⁸,—R⁶C(O)R⁹C(S)SR⁸, —R⁶C(O)R⁹C(NR⁷)SR⁸, —R⁶OR⁹OR⁷, —R⁶C(O)R⁹N(R⁷)R⁹N(R⁷)₂,—R⁶C(O)R⁹N(R⁷)R⁹OR⁷ and —R⁶C(O)N(R⁷)R⁹OR⁷; each R² is independentlyselected from hydrogen, halo, nitro, cyano, optionally substitutedalkyl, —OR¹², —SR¹², —N(R¹²)₂, —S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —C(O)SR¹², and —N(R¹²)S(O)_(t)R¹³; R³ is hydrogen, halo,nitro, cyano, optionally substituted alkyl, —OR¹², —SR¹², —N(R¹²)₂,—S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², or—N(R¹²)S(O)_(t)R¹³; t is 1 or 2; and each R⁵ is independently hydrogen,or optionally substituted alkyl; each R⁶ is independently a direct bond,an optionally substituted alkylene chain, or an optionally substitutedalkenylene chain; each R⁷ is independently selected from (i) or (ii)below (i) R⁷ is selected from a group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl, or (ii) two (R⁷)s together withthe atom to which they are attached form an optionally substitutedheterocyclyl or optionally substituted heteroaryl; R⁸ is independentlyselected from the group consisting of optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroaralkyl; each R⁹ is independently an optionallysubstituted alkylene chain or an optionally substituted alkenylenechain; each R¹² is independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroaralkyl; and R¹³ isindependently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl; as a single stereoisomer, amixture of stereoisomers, a racemic mixture of stereoisomers, or as apharmaceutically acceptable salt thereof.
 19. The compound of claim 18corresponding to the formula (III):

wherein: X is —S—, —N(R⁵)— or —O—; X¹ is —C(R¹⁰)—, or —N—; X² is —O— or—S—; where each R¹⁰ is independently selected from hydrogen, halo,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heterocyclyl andoptionally substituted heteroaryl; and the remainder of n, R⁰, R¹, R²,R³ and R⁵ are as defined in claim 20; as a single stereoisomer, amixture of stereoisomers, a racemic mixture of stereoisomers, or as apharmaceutically acceptable salt thereof.
 20. The compound of claim 18,wherein R¹ is independently selected from the group consisting of halo,optionally substituted alkyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclyl, optionally substitutedheteroaralkyl, optionally substituted heteroaryl, —R⁶OR⁷, —R⁶SR⁷,—R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂, —R⁶C(O)R⁷, —R⁶C(S)R⁷, —R⁶C(NR⁷)R⁷, —R⁶C(O)OR⁷,—R⁶C(O)N(R⁷)R⁹N(R⁷)₂, —R⁶OC(O)R⁷, —R⁶C(NR⁷)OR⁷, —R⁶C(O)N(R⁷)₂,—R⁶N(R⁷)C(O)R⁸, —R⁶OR⁹N(R⁷)₂, —R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂,—R⁶—OR⁹OR⁷, —R⁶—OR⁹N(R⁷)₂, —R⁶C(O)R⁹N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)R⁹N(R⁷)R⁹OR⁷and —R⁶C(O)N(R⁷)R⁹OR⁷ wherein: t is 1 or 2; each R⁶ is independently adirect bond, an optionally substituted alkylene chain, or an optionallysubstituted alkenylene chain; each R⁷ is independently selected from (i)or (ii) below (i) R⁷ is selected from the group consisting of hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl, or (ii) two (R⁷)s together withthe atom to which they are attached form an optionally substitutedheterocyclyl or optionally substituted heteroaryl; R⁸ is independentlyselected from the group consisting of optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroaralkyl; and each R⁹ is independently an optionallysubstituted alkylene chain or an optionally substituted alkenylenechain.
 21. The compound of claim 20, wherein R¹ is —R⁶OR⁷, —R⁶SR⁷,—R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂, —R⁶C(O)R⁷, —R⁶C(S)R⁷, —R⁶C(NR⁷)R⁷, —R⁶C(O)OR⁷,—R⁶C(O)N(R⁷)R⁹N(R⁷)₂, —R⁶OC(O)R⁷, —R⁶C(NR⁷)OR⁷, —R⁶C(O)N(R⁷)₂,—R⁶N(R⁷)C(O)R⁸, —R⁶OR⁹N(R⁷)₂, —R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶OR⁹OR⁷,—R⁶OR⁹N(R⁷)₂, —R⁶C(O)R⁹N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)R⁹N(R⁷)R⁹OR⁷ or—R⁶C(O)N(R⁷)R⁹OR⁷; and each R⁶ is independently a direct bond, anoptionally substituted alkylene chain, or an optionally substitutedalkenylene chain; and R⁷, when attached singly to an atom, is eachindependently selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroaralkyl, and when attached doubly to thesame atom, together forms an optionally substituted heterocyclyl oroptionally substituted heteroaryl.
 22. The compound of claim 19corresponding to the formula (IIIa):

as a single stereoisomer, a mixture of stereoisomers, a racemic mixtureof stereoisomers, or as a pharmaceutically acceptable salt thereof. 23.The compound of claim 19 corresponding to the formula (IV)

wherein: K is —(CH₂)_(q)—, —C(O), —(CH₂)_(q)O—, —(CH₂)_(q)O(CH₂)_(q)—,—(CH₂)_(q)C(O)—, —(CH₂)_(q)C(O)NH(CH₂)_(q)—, —C(O)NH(CH₂)_(q)—,—O(CH₂)_(q)—, —OC(O)—, —OC(O)(CH₂)_(q)— or a direct bond; X is —S—,—N(R⁵)— or —O—; X¹ is —C(R¹⁰)—, or —N—; X² is —O— or S—; Y is —O—, —S—,—S(O)—, —S(O)₂—, —N(R¹⁴)—, —C(H)R¹⁵—, or —C(O)—; q is an integer from 1to 4; p is an integer from 0 to 2; R¹⁰ is independently selected fromhydrogen, halo, optionally substituted alkyl, optionally substitutedcycloalkyl, or optionally substituted aryl; R¹⁴ is independently,hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heteroaryl, optionally substitutedaryl, S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, or —C(O)SR¹²; R¹⁵is independently, hydrogen, halo, nitro, cyano, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheteroaryl, optionally substituted aryl, —OR¹², —SR¹², —N(R¹²)₂,—S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², or—N(R¹²)S(O)_(t)R¹³; t is 1 or 2; and as a single stereoisomer, a mixtureof stereoisomers, a racemic mixture of stereoisomers, or as apharmaceutically acceptable salt thereof.
 24. The compound of claim 23,wherein X¹ is —N— and X² is —O—.
 25. The compound of claim 23, wherein Yis —N(R¹⁴); R¹⁴ is alkyl or —S(O)_(t)R¹³; t is 1 or 2 and R¹³ is alkyl.26. The compound of claim 25, wherein R¹⁴ is methyl, ethyl or—S(O)_(t)R¹³; t is 2 and R¹³ is methyl.
 27. The compound of claim 23,wherein the compound is of formula (V):

wherein K is —O(CH₂)_(q)—, —C(O), —C(O)NH(CH₂)_(q)—, —(CH₂)_(q)O—, or—(CH₂)_(q)O(CH₂)_(q)—; p is an integer from 0 to 2; each q isindependently an integer from 1 to 4; X¹ is —N—; X² is —O—; Y is —O—,—S—, —N(R¹⁴)— or —C(H)R¹⁵—, m is 0, 1, or 2; R¹⁴ is hydrogen, optionallysubstituted alkyl, —C(O)OR¹², —C(O)SR¹², —C(O)NR¹² or —S(O)_(t)R¹³; R¹⁵is hydrogen or optionally substituted alkyl; R¹³ is optionallysubstituted alkyl; and t is 1 or 2; as a single stereoisomer, a mixtureof stereoisomers, a racemic mixture of stereoisomers, or as apharmaceutically acceptable salt thereof.
 28. The compound of claim 27,wherein the compound is of formula (Va):

wherein K is —O(CH₂)_(q)—, —(CH₂)_(q)O—, —(CH₂)_(q)— or—(CH₂)_(q)O(CH₂)_(q)—; each q is independently 1 to 4; Y is —O—, —S—, or—N(R¹⁴)—; R¹⁴ is hydrogen, optionally substituted lower alkyl, or—S(O)_(t)R¹³; R¹³ is lower alkyl; and t is 1 or
 2. 29. The compound ofclaim 22, wherein R¹ is halo, alkyl, —R⁶OR⁷, —R⁶N(R⁷)₂, —R⁶C(O)OR⁷,—R⁹OR⁹OR⁷, —R⁶OR⁹N(R⁷)₂, —R⁶C(O)N(R⁷)R⁹(R⁷)₂, —R⁶C(O)R⁹N(R⁷)R⁹OR⁷ or—R⁶C(O)N(R⁷)R⁹OR⁷; and R⁷ is hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroaralkyl.
 30. The compound of claim 29, wherein R¹ isfluoro, methyl, ethyl, hydroxy, methoxy, diethylamino or carboxy. 31.The compound of claim 1 selected from the group consisting of:3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-morpholin-4-yl-ethyl)-propionamide;3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-piperidin-1-yl-ethyl)-propionamide;3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)-propionamide;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazin-1-yl)-benzo[d]imidazo[2,1b]thiazol-2-yl]-phenyl}-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-piperidin-1-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[3-(4-methanesulfonyl-piperazin-1-yl)-propoxy]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-urea;N-(5-tert-Butyl-isoxazol-3-yl)-N′-(4-{7-[3-(4-ethyl-piperazin-1-yl)propyl]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-3-oxo-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;3-(5-tert-Butyl-isoxazol-3-yl)-1-methyl-1-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(3-morpholin-4-yl-propyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-morpholin-4-yl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[7-(3-piperidin-1-yl-propyl)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[5-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;2-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-morpholin-4-yl-ethyl)-acetamide;2-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-piperidin-1-yl-ethyl)-acetamide;2-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-ethyl-piperazin-1-yl)-2-oxo-ethyl]-benzo[d]imidazo[2,1-b]thiazol-2-yl}-phenyl)-ureaand1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-morpholin-4-ylmethyl-imidazo[2,1-b][1,3]benzothiazol-2-yl)-phenyl]-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(4-ethyl-piperazin-1-ylmethyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-piperidin-1-ylmethyl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-morpholin-4-yl-2-oxo-ethyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-morpholin-4-yl-ethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-piperidin-1-yl-ethyl)-imidazo[2,1-b][1,3]benzothiazol-2-yl]-phenyl}-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-(4-{7-[2-(4-ethyl-piperazin-1-yl)-ethyl]-imidazo[2,1-b][1,3]benzothiazol-2-yl}-phenyl)-urea;N-(5-tert-Butyl-isoxazol-3-yl)-N′-{4-[6-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea;2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylicacid (2-piperidin-1-yl-ethyl)-amide;2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide;2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylicacid (2-diethylamino-ethyl)-amide;1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-ethyl-piperazine-1-carbonyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(piperazine-1-carbonyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;and1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(4-methyl-piperazine-1-carbonyl)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea.32. The compound of claim 1 selected from the group consisting of:1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-hydroxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-methoxy-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[7-(2-diethylamino-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea;ethyl{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}acetate;3-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}aceticacid; pyrrolidine-2-carboxylic acid2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-ylester; ethyl3-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoate;3-{2-[4-({[(5-tert-Butylisoxazol-3-yl)amino]carbonyl}amino)phenyl]imidazo[2,1-b][1,3]benzothiazol-7-yl}propanoicacid3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N,N-diethyl-propionamide;2-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-diethylamino-ethyl)-acetamide;3-(2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl)-N-(2-diethylamino-ethyl)-propionamide;2-Amino-3-methyl-butyric acid2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-ylester;2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylicacid ethyl ester, and2-{4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazole-7-carboxylicacid.
 33. The compound of claim 1 selected from the group consisting of:1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-fluoro-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea;and1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(7-methyl-benzo[d]imidazo[2,1-b]thiazol-2-yl)-phenyl]-urea.34. A composition comprising an effective amount of a compound of claim1 and a pharmaceutically acceptable carrier, excipient or diluent. 35.The composition according to claim 34 further comprising a therapeuticagent selected from a chemotherapeutic agent, an anti-proliferativeagent, an anti-inflammatory agent, an immunomodulatory agent and animmunosuppressive agent.
 36. A compound of formula (I),

wherein bond b is a single bond or double bond; X is —S—, —N(R⁵)— or—O—; Z¹ and Z³ are each independently —N(R⁵)—, —(CH₂)_(q)—, —O—, —S—, ora direct bond; Z² is —C(O)— or —C(S)—; m is an integer from 1 to 2; n isan integer from 1 to 3; each q is independently an integer from 1 to 4;R⁰ is hydrogen, halo, hydroxy, optionally substituted alkyl, oroptionally substituted alkoxy; each R¹ is independently selected fromthe group consisting of halo, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heteroaralkyl, optionallysubstituted heteroaralkenyl, —R⁶OR⁷, —R⁶SR⁷, —R⁶S(O)_(t)R⁸, —R⁶N(R⁷)₂,—R⁶—OR⁹OR⁷, —R⁶CN, —R⁶C(O)R⁷, —R⁶C(S)R⁷, —R⁶C(NR⁷)R⁷, —R⁶C(O)OR⁷,—R⁶C(S)OR⁷, —R⁶C(NR⁷)OR⁷, —R⁶C(O)N(R⁷)₂, —R⁶C(S)N(R⁷)₂, —R⁶C(NR⁷)N(R⁷)₂,—R⁶C(O)N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)SR⁸, —R⁶C(S)SR⁸, —R⁶C(NR⁷)SR⁸,—R⁶S(O)_(t)OR⁷, —R⁶S(O)_(t)N(R⁷)₂, —R⁶S(O)_(t)N(R⁷)N(R⁷)₂,—R⁶S(O)_(t)N(R⁷)N═C(R⁷)₂, —R⁶S(O)_(t)N(R⁷)C(O)R⁸,—R⁶S(O)_(t)N(R⁷)C(O)N(R⁷)₂, —R⁶S(O)_(t)N(R⁷)C(NR⁷)N(R⁷)₂,—R⁶N(R⁷)C(O)R⁸, —R⁶N(R⁷)C(O)OR⁸, —R⁶N(R⁷)C(O)SR⁸, —R⁶N(R⁷)C(NR⁷)SR⁸,—R⁶N(R⁷)C(S)SR⁸, —R⁶N(R⁷)C(O)N(R⁷)₂, —R⁶N(R⁷)C(NR⁷)N(R⁷)₂,—R⁶N(R⁷)C(S)N(R⁷)₂, —R⁶N(R⁷)S(O)_(t)R⁸, —R⁶OC(O)R⁸, —R⁶OC(NR⁷)R⁸,—R⁶OC(S)R⁸, —R⁶OC(O)OR⁸, —R⁶OC(NR⁷)OR⁸, —R⁶OC(S)OR⁸, —R⁶OC(O)SR⁸,—R⁶OC(O)N(R⁷)₂, —R⁶OC(NR⁷)N(R⁷)₂, —R⁶OC(S)N(R⁷)₂, —R⁶OR⁹N(R⁷)₂,—R⁶SR⁹N(R⁷)₂, —R⁶N(R⁷)R⁹N(R⁷)₂, —R⁶C(O)R⁹C(O)R⁷, —R⁶C(O)R⁹C(S)R⁷,—R⁶C(O)R⁹C(NR⁷)R⁷, —R⁶C(O)R⁹C(O)OR⁷, —R⁶C(O)R⁹C(S)OR⁷,—R⁶C(O)R⁹C(NR⁷)OR⁷, —R⁶C(O)R⁹C(O)N(R⁷)₂, —R⁶C(O)R⁹C(S)N(R⁷)₂,—R⁶C(O)R⁹C(NR⁷)N(R⁷)₂, —R⁶C(O)R⁹C(O)SR⁸, —R⁶C(O)R⁹C(S)SR⁸,—R⁶C(O)R⁹C(NR⁷)SR⁸, —R⁶OR⁹OR⁷, —R⁶C(O)R⁹N(R⁷)R⁹N(R⁷)₂,R⁶C(O)R⁹N(R⁷)R⁹OR⁷ and —R⁶C(O)N(R⁷)R⁹OR⁷; each R² is independentlyselected from hydrogen, halo, nitro, cyano, optionally substitutedalkyl, —OR¹², —SR¹², —N(R¹²)₂, —S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹²,—C(O)N(R¹²)₂, —C(O)SR¹², and —N(R¹²)S(O)_(t)R¹³; R³ is hydrogen, halo,nitro, cyano, optionally substituted alkyl, —OR¹², —SR¹², —N(R¹²)₂,—S(O)_(t)R¹³, —C(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂, —C(O)SR¹², or—N(R¹²)S(O)_(t)R¹³; t is 1 or 2; R⁴ is selected from the groupconsisting of optionally substituted heterocyclyl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, and optionally substituted aryl; each R⁵ isindependently hydrogen, or optionally substituted alkyl; each R⁶ isindependently a direct bond, an optionally substituted alkylene chain,or an optionally substituted alkenylene chain; each R⁷ is independentlyselected from (i) or (ii) below (i) R⁷ is selected from a groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroaralkyl, or (ii) two R⁷ groups together with the atom to whichthey are attached form an optionally substituted heterocyclyl oroptionally substituted heteroaryl; R⁸ is independently selected from thegroup consisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroaralkyl; each R⁹is independently an optionally substituted alkylene chain or anoptionally substituted alkenylene chain; each R¹² is independentlyselected from the group consisting of hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroaralkyl; and R¹³ is independently selected from thegroup consisting of optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroaralkyl; as asingle stereoisomer, a mixture of stereoisomers, a racemic mixture ofstereoisomers, or as a pharmaceutically acceptable salt thereof.
 37. Acompound of formula: